Method for producing polyalkylene glycol derivative having amino group at end, polymerization initiator for use in the same, and alcohol compound as raw material for the polymerization initiator

ABSTRACT

A method for producing a narrowly distributed and high-purity polyalkylene glycol derivative having an amino group at an end, a polymerization initiator for use in the method, and a precursor of the polymerization initiator are provided. 
     The present invention provides: a method for producing a polyalkylene glycol derivative having an amino group at an end, using, as a polymerization initiator, a compound represented by the general formula (I); a compound represented by the following general formula (I); and a precursor thereof: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R A   1a  and R A   1b  each independently represent a protective group of the amino group, or one of R A   1a  and R A   1b  represents H and the other represents a protective group of the amino group, or R A   1a  and R A   1b  bind to each other to represent a cyclic protective group forming a ring; R A   2  represents a linear, branched, or cyclic hydrocarbon group having 1 to 6 carbon atoms; R A   3  represents a single bond, or a linear, branched, or cyclic hydrocarbon group having 1 to 20 carbon atoms, and the hydrocarbon group may contain a heteroatom; the total number of carbon atoms (or the total number of carbon atoms and heteroatoms) of R A   2  and R A   3  is 4 or more; and M represents an alkali metal.

RELATED APPLICATIONS

This application is a divisional of and claims priority to U.S. patentapplication Ser. No. 14/959,318, filed Dec. 4, 2015, now allowed, whichclaims priority from Japanese Patent Application No. 2014-246046, filedDec. 4, 2014 and Japanese Application No. 2015-151012, filed Jul. 30,2015, the disclosures of each of which are incorporated by referenceherein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to a method for producing a polyalkyleneglycol derivative having a terminal amino group, a polymerizationinitiator for use in the same, and an alcohol compound as a raw materialof the polymerization initiator.

Recently, in the drug delivery system, a method for encapsulating drugsin a polymer micelle using a block copolymer formed from a hydrophilicsegment and a hydrophobic segment has been proposed (refer to, forexample, Japanese Patent No. 2690276, Japanese Patent No. 2777530, andJapanese Patent Application Laid-Open No. 11-335267). By using themethod, the polymer micelle functions as a carrier for drugs, producingvarious effects including sustained release of drugs in vivo andconcentrated dosage at an affected region.

As the hydrophilic segment, many examples with use of a polyalkyleneglycol skeleton are proposed (refer to, for example, Japanese Patent No.2690276, Japanese Patent No. 2777530, and Japanese Patent ApplicationLaid-Open No. 11-335267). A compound having a polyalkylene glycolskeleton has low toxicity in vivo, and enables excretion by the kidneyto be delayed. Consequently, in comparison with a compound having nopolyalkylene glycol skeleton, the retention time in blood can beprolonged. As a result, with use of a drug micellized with apolyalkylene glycol derivative, the dosage amount or dosage frequencycan be reduced.

Among polyalkylene glycol derivatives, a compound having an amino groupat an end can lead to a block copolymer composed of a polyalkyleneglycol skeleton and an amino acid skeleton through a ring-openingpolymerization reaction with α-amino acid-N-carboxy anhydride. Manyexamples with use of the produced block copolymer for encapsulatingdrugs in a polymer micelle are proposed (refer to, for example, JapanesePatent No. 2690276, Japanese Patent No. 2777530, and Japanese PatentApplication Laid-Open No. 11-335267).

Synthesis methods of such polyalkylene glycol derivatives having anamino group at an end are also known (refer to, for example, JapanesePatent No. 3050228 and Japanese Patent No. 3562000). In these methods,after polymerization of an alkylene oxide with use of a metal salt ofmonohydric alcohol as a polymerization initiator, a polymer end isconverted to a hydroxyl group, and then to a 2-cyanoethoxy group,finally leading to an amino group-containing substituent group(3-amino-1-propoxy group) through hydrogen reduction of the cyano group.

Other methods for synthesizing a polyalkylene glycol derivative havingan amino group include, for example, a method in which ethylene oxide ispolymerized with a polymerization initiator the amino group of which issilyl-protected, and then deprotection is performed to lead an aminogroup (refer to Bioconj. Chem. 1992, 3, 275-276, and Japanese Patent No.4581248). However, in this method, there is a problem that the end islimited to a 2-amino-1-ethoxy group. Moreover, it is considered that thereactivity is low and the problem is that a long time, as long as 96hours, are required for increasing the molecular weight up to 6000(refer to Bioconj. Chem. 1992, 3, 275-276).

SUMMARY OF THE INVENTION

As disclosed in in Japanese Patent No. 3050228, it is difficult tocompletely dissolve the metal salts of monohydric alcohol used as apolymerization initiator in polymerization solvents (organic solventssuch as, for example, tetrahydrofuran (abbreviated as “THF”)) in manycases. In these cases, in order to dissolve the metal salts inpolymerization solvents, an excess amount of alcohol that is a initiatorraw material has to be left during synthesis of the metal salts (forexample, in Japanese Patent No. 3050228, 13-mol of methanol to 2 mol ofsodium methoxide that is a polymerization initiator). Due to thepresence of these alcohols in a reaction system, however, reduction inthe polymerization rate is unavoidable. Consequently, crucial reactionconditions such as high temperature and high pressure are required forincreasing the polymerization rate. Moreover, when the polymerizationinitiator does not dissolve in a polymerization solvent, the system doesnot become uniform, and therefore there is a problem in that thevariation of the obtained polyalkylene glycol derivatives becomes broadbecause polymerization only progresses from the dissolved polymerizationinitiator.

Monohydric alcohols contain a trace amount of water in many cases. Thepolymerization of an alkylene oxide with a polymerization initiatorprepared in a water-containing state produces a polymer compound havinga hydroxyl group at both ends as by-product (hereinafter abbreviated as“diol polymer”). In the case of monohydric alcohols having a boilingpoint sufficiently higher than that of water, the water content can bereduced by dehydration under reduced pressure. However, since methanolfor use in the case in which an end is, for example, a methyl group, hasa boiling point lower than that of water, the water content cannot beremoved by dehydration under reduced pressure. Therefore, thepolymerization of an alkylene oxide with a metal salt prepared by usingmethanol, unavoidably produces a diol polymer. Since various physicalproperties of diol polymer such as structure and molecular weight aresimilar to those of the target substance, separation and purificationare extremely difficult. When the subsequent reactions proceed in thepresence of diol polymer as an impurity, a polymer including an aminogroup at both ends is produced unless proper reaction conditions areselected. The direct use of the polymer which includes such an impuritymay result in the possibility that an intended performance cannot beachieved in designing a polymer micellizing agent. Therefore, in thepolymerization reaction, the water content is required to be reduced tobe as low as possible.

In the synthesis methods described in Japanese Patent No. 3050228 andJapanese Patent No. 3562000, a cyano group is converted to anaminomethyl group through hydrogen reduction with a Raney nickelcatalyst. In these methods, there is concern over a possibility thattrace amounts of metals will be mixed in the final product depending onthe use of the polyalkylene glycol derivative in some cases.Furthermore, the reaction is generally considered to require hightemperature, there have been problems yet to be solved in that a targetproduct cannot be obtained with a high yield rate because β-eliminationof acrylonitrile progresses associated with reaction at a hightemperature, and that there is a risk that secondary and tertiary aminesare produced due to addition reaction of an amine to an imine that is anintermediate in nitrile reduction and polyacrylonitrile is by-produced.

As a method for synthesizing a polyalkylene glycol derivative having anamino group at an end without using a heavy metal, a method isconsidered in which an alkylene oxide is polymerized using, as apolymerization initiator, an alkoxide the amino group of which isprotected. For example, in the case in which a silyl group is used as aprotective group of the amino group, it is extremely difficult toselectively synthesize an alcohol, only the amino group of which issilylated, because the silicon-nitrogen bond is weaker than thesilicon-oxygen bond, and therefore, a synthesis example of the alcoholhas not yet been reported.

The present invention intends to solve the problems of the conventionaltechnologies, and to provide: a method for producing a narrowlydistributed and high-purity polyalkylene glycol derivative having anamino group at an end; and a polymerization initiator for use in themethod.

Through intensive research for achieving the objects, the presentinventors have found that use of a compound, the amino group of which isprotected by a protective group, the compound having a sufficientsolubility to polymerization solvents, as a polymerization initiator,makes it possible: to polymerize an alkylene oxide under mildconditions; to suppress production of a diol polymer; further, to removethe diol polymer when produced; besides, to achieve prevention of mixingof heavy metals and prevention of production of by-products; and finallyto lead to a high-purity and narrowly distributed polyalkylene glycolderivative having an amino group at an end, and have completed thepresent invention.

That is to say, the present invention relates to a method for producinga polyalkylene glycol derivative having an amino group at an end with acompound represented by the following general formula (I) as apolymerization initiator, the method including at least a step ofreacting the polymerization initiator with an alkylene oxide.

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently represent aprotective group of the amino group, or one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, or R_(A) ^(1a) and R_(A) ^(1b) bind to eachother to represent a cyclic protective group forming a ring togetherwith a nitrogen atom of the amino group;

R_(A) ² represents a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms;

R_(A) ³ represents a single bond, or a linear divalent hydrocarbon grouphaving 1 to 20 carbon atoms, or a branched or cyclic divalenthydrocarbon group having 3 to 20 carbon atoms, and the hydrocarbon groupmay contain a heteroatom;

a total number of carbon atoms of R_(A) ² and R_(A) ³ is 4 or more, orin a case in which R_(A) ³ contains a heteroatom, a total number ofcarbon atoms and heteroatoms of R_(A) ² and R_(A) ³ is 4 or more; and

M represents an alkali metal.

According to another embodiment, the present invention relates to amethod for producing a polyalkylene glycol derivative having an aminogroup at an end including the following steps a) to step c):

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently represent aprotective group of the amino group, or one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, or R_(A) ^(1a) and R_(A) ^(1b) bind to eachother to represent a cyclic protective group forming a ring togetherwith a nitrogen atom of the amino group;

R_(A) ² represents a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms; R_(A) ³ represents a single bond, or a lineardivalent hydrocarbon group having 1 to 20 carbon atoms, or a branched orcyclic divalent hydrocarbon group having 3 to 20 carbon atoms, and thehydrocarbon group may contain a heteroatom;

a total number of carbon atoms of R_(A) ² and R_(A) ³ is 4 or more, orin a case in which R_(A) ³ contains a heteroatom, a total number ofcarbon atoms and heteroatoms of R_(A) ² and R_(A) ³ is 4 or more;

R_(A) ⁴ represents a hydrogen atom, or a linear, branched, or cyclichydrocarbon group that may be substituted, the hydrocarbon group having1 to 12 carbon atoms, and the hydrocarbon group may contain aheteroatom;

R_(A) ⁵ represents an alkylene group having 2 to 8 carbon atoms;

M represents an alkali metal; and

n represents an integer of 1 to 450;

Step a)

a step of reacting a polymerization initiator represented by the generalformula (I) with an alkylene oxide in a polymerization solvent to obtaina compound represented by the following general formula (I-1):

wherein R_(A) ^(1a), R_(A) ^(1b), R_(A) ², R_(A) ³ and R_(A) ⁵ are thesame as defined in the general formulas (II) and (III) as above;

M represents an alkali metal and is the same as M in the general formula(I) as above; and

r represents an integer of 1 to 445;

Step b)

a step of reacting the compound represented by the general formula (I-1)with a compound represented by the following general formula (I-2) toobtain a compound represented by the general formula (II):R_(A) ⁴OR_(A) ⁵)_(k)L  (1-2)

wherein R_(A) ⁴ and R_(A) ⁵ are the same as defined in the generalformulas (II) and (III);

k represents an integer of 0 to 5; and

L represents a leaving group; and

Step c)

a step of deprotecting the compound represented by the general formula(II) to obtain a compound represented by the general formula (III).

According to yet another embodiment, the present invention relates to aprotected amino group-containing alcohol compound represented by thefollowing general formula (i):

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently represent aprotective group of the amino group, or one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, or R_(A) ^(1a) and R_(A) ^(1b) bind to eachother to represent a cyclic protective group forming a ring togetherwith a nitrogen atom of the amino group;

R_(A) ² represents a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms;

R_(A) ³ represents a single bond, or a linear divalent hydrocarbon grouphaving 1 to 20 carbon atoms, or a branched or cyclic divalenthydrocarbon group having 3 to 20 carbon atoms, and the hydrocarbon groupmay contain a heteroatom; and

total number of carbon atoms of R_(A) ² and R_(A) ³ is 4 or more, or ina case in which R_(A) ³ contains a heteroatom, a total number of carbonatoms and heteroatoms of R_(A) ² and R_(A) ³ is 4 or more.

According to still yet another embodiment, the present invention relatesto a metal salt of a protected amino group-containing alcohol compound,the metal salt represented by the following general formula (I):

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently represent aprotective group of the amino group, or one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, or R_(A) ^(1a) and R_(A) ^(1b) bind to eachother to represent a cyclic protective group forming a ring togetherwith a nitrogen atom of the amino group;

R_(A) ² represents a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms;

R_(A) ³ represents a single bond, or a linear divalent hydrocarbon grouphaving 1 to 20 carbon atoms, or a branched or cyclic divalenthydrocarbon group having 3 to 20 carbon atoms, and the hydrocarbon groupmay contain a heteroatom;

a total number of carbon atoms of R_(A) ² and R_(A) ³ is 4 or more, orin a case in which R_(A) ³ contains a heteroatom, a total number ofcarbon atoms and heteroatoms of R_(A) ² and R_(A) ³ is 4 or more; and

M represents an alkali metal.

By using the method for producing a polyalkylene glycol derivativehaving an amino group at an end according to the present invention,polymerization performed substantially in the absence of an alcohol,that is a polymerization initiator raw material and that is a cause ofreduction in polymerization rate, becomes possible. The polymerizationof an alkylene oxide can be performed under milder conditions thanconventional conditions. Furthermore, production of impurities such as adiol polymer attributable to a trace amount of water is suppressed. Evenif water is mixed, and resulting in production of polymer impurities,the polymer impurities can be removed by separation and purification,making it possible to produce a high-purity and narrowly distributedpolyalkylene glycol derivative. Moreover, in the case in which themethod also includes a purification step, since freeze drying is notneeded during the purification and extraction of the polyalkylene glycolderivative, the method is further advantageous in that the polyalkyleneglycol derivative can be produced on an industrial scale andsimplification of facilities and processes can be realized. Furthermore,by using the polymerization initiator in which the amino group isprotected, the reduction method using a heavy metal does not have to beused to prevent for by-products being mixed, and therefore, it becomespossible to reduce a risk of mixing heavy metal impurities andby-products that should be avoided in medical supplies. Furthermore,since the polymerization initiator uniformly dissolves in the system,the polyalkylene glycol derivative produced by the production methodaccording to the present invention is narrowly distributed, capable ofbeing extremely advantageously used in leading to a block copolymerformed from a hydrophilic segment and a hydrophobic segment, for use inthe field of drug delivery systems. Furthermore, the alcohol compoundthe amino group of which is protected and the alkali metal salt thereofaccording to the present invention may be used as a more usefulpolymerization initiator and a precursor thereof in place ofconventional polymerization initiators and precursors thereof in themethod for producing a polyalkylene glycol derivative, and therefore areextremely useful.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention now will be described more fully hereinafter inwhich embodiments of the invention are provided with reference to theaccompanying drawings. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is forthe purpose of describing particular embodiments only and is notintended to be limiting of the invention. As used in the description ofthe invention and the appended claims, the singular forms “a”, “an” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise. Unless otherwise defined, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All references cited are incorporated herein byreference in their entirety.

The present invention is a method for producing a polyalkylene glycolderivative having an amino group at an end, using a compound representedby the following general formula (I) as a polymerization initiator, themethod including at least a step of reacting the polymerizationinitiator with an alkylene oxide. The present invention, according to anembodiment, sequentially performs the following steps a) to c)(hereinafter, this embodiment is sometimes referred to as “Embodiment1”):

Step a)

a step of reacting a polymerization initiator represented by the generalformula (I) with an alkylene oxide in a polymerization solvent to obtaina compound represented by the following general formula (I-1);

Step b)

a step of reacting the compound represented by the general formula (I-1)with a compound represented by the following general formula (I-2) toobtain a compound represented by the following general formula (II); and

Step c)

a step of deprotecting the compound represented by the general formula(II) to obtain a compound represented by the general formula (III).

In the general formulas (I), (I-1), and (II), R_(A) ^(1a) and R_(A)^(1b) each independently represent a protective group of the aminogroup, or one of R_(A) ^(1a) and R_(A) ^(1b) represents a hydrogen atomand the other represents a protective group of the amino group, or R_(A)^(1a) and R_(A) ^(1b) bind to each other to represent a cyclicprotective group forming a ring together with a nitrogen atom of theamino group. The protective group is preferably a protective group thatis deprotectable without using a heavy metal catalyst. The kinds ofprotective groups represented by R_(A) ¹³ and/or R_(A) ^(1b) may beexemplified by classifying the protective groups into the following(P-1) to (P-4), although this is not limited thereto.

(P-1) Protective group of a structure represented by Si(R¹)₃(trialkylsilyl group)

In the case in which R_(A) ^(1a) and R_(A) ^(1b) in the general formulas(I), (I-1), and (II) each independently represent a protective group ofthe amino group, and in the case in which one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, R_(A) ^(1a) and/or R_(A) ^(1b) may be aprotective group of a structure represented by Si(R¹)₃ (trialkylsilylgroup).

In the structure represented by Si(R¹)₃, R¹ each independently representa linear monovalent hydrocarbon group having 1 to 6 carbon atoms, or abranched or cyclic monovalent hydrocarbon group having 3 to 6 carbonatoms, or R¹ may bind to each other to form a 3 to 6 membered ringtogether with a silicon atom having bonds with R¹. Examples of R¹include a methyl group, an ethyl group, an n-propyl group, an isopropylgroup, an n-butyl group, an isobutyl group, a tert-butyl group, ann-pentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, and a cyclohexyl group. Moreover, in thecase in which R¹ bind to each other to form a ring together with asilicon atom, examples of R¹ include a group obtained by eliminating onehydrogen atom from the above-listed groups.

Preferred specific examples of the protective group having a structurerepresented by Si(R¹)₃ include a trimethylsilyl group, a triethylsilylgroup, and a tert-butyldimethylsilyl group, although this is not limitedthereto.

(P-2) Protective Group of a Structure Represented by R_(A) ⁶OCO

In the case in which R_(A) ^(1a) and R_(A) ^(1b) in the general formulas(I), (I-1), and (II) each independently represent a protective group ofthe amino group, and in the case in which one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, R_(A) ^(1a) and/or R_(A) ^(1b) may be aprotective group of a structure represented by R_(A) ⁶OCO.

In the structure represented by R_(A) ⁶OCO, R_(A) ⁶ represents a residueof a monovalent hydrocarbon having 1 to 20 carbon atoms, and the residuemay contain a halogen atom, an oxygen atom, a nitrogen atom, a sulfuratom, a silicon atom, a phosphorus atom, or a boron atom.

As the protective group represented by the structure of R_(A) ⁶OCO, amethyloxycarbonyl group, an ethyloxycarbonyl group, anisobutyloxycarbonyl group, a tert-butyloxycarbonyl group, atert-amyloxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group, a2-trimethylsilylethyloxycarboyl group, a phenylethyloxycarbonyl group, a1-(1-adamantyl)-1-methylethyloxycarbonyl group, a1,1-dimethyl-2-haloethyloxycarbonyl group, a1,1-dimethyl-2,2-dibromoethyloxycarbonyl group, a1,1-dimethyl-2,2,2-trichloroethyloxycarbonyl group, a1-methyl-1-(4-biphenyl)ethyloxycarbonyl group, a1-(3,5-di-t-butylphenyl)-1-methylethyloxycarbonyl group, a2-(2′-pyridyl)ethyloxycarbonyl group, a 2-(4′-pyridyl)ethyloxycarbonylgroup, a 2-(N,N-dicyclohexylcarboxyamide)ethyloxycarbonyl group, a1-adatnantyloxycarbonyl group, a vinyloxycarbonyl group, anallyloxycarbonyl group, a 1-isopropylallyloxycarbonyl group, acinnamyloxycarbonyl group, a 4-nitrocinnamyloxycarbonyl group, a8-quinolyloxycarbonyl group, a N-hydroxypiperidinyloxycarbonyl group, analkyldithiocarbonyl group, a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, ap-bromobenzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a2,4-dichlorobenzyloxycarbonyl group, a 4-methylsulfinylbezyloxycarbonylgroup, a 9-anthrylmethyloxycarbonyl group, a diphenylmethyloxycarbonylgroup, a 9-fluorenylmethyloxycarbonyl group, a9-(2,7-dibromo)fluorenylmethyloxycarbonyl group, a2,7-di-t-butyl-[9-(10,10-dioxo-thioxanthenyl)]methyloxycarbonyl group, a4-methoxyphenacyloxycarbonyl group, a 2-methylthioethyloxycarbonylgroup, a 2-methylsulfonylethyloxycarbonyl group, a2-(p-toluenesulfonyl)ethyloxycarbonyl group, a[2-(1,3-dithianyl)]methyloxycarbonyl group, a4-methylthiophenyloxycarbonyl group, a 2,4-dimethylthiophenyloxycarbonylgroup, a 2-phosphonioethyloxycarbonyl group, a2-triphenylphosphonioisopropyloxycarbonyl group, a1,1-dimethyl-2-cyanoethyloxycarbonyl group, anm-chloro-p-acyloxybenzyloxycarbonyl group, ap-(dihydroxyboryl)benzyloxycarbonyl group, a5-benzoisooxazolylmethyloxycarbonyl group, a2-(trifluoromethyl)-6-chromonylmethyloxycarbonyl group, aphenyloxycarbonyl group, an m-nitrophenyloxycarbonyl group, a3,5-dimethoxybenzyloxycarbonyl group, an o-nitrobenzyloxycarbonyl group,a 3,4-dimethoxy-6-nitrobenzyloxycarbonyl group, and aphenyl(o-nitrophenyl)methyloxycarbonyl group are included. Among them,the tert-butyloxycarbonyl group, the 2,2,2-trichloroethyloxycarbonylgroup, the allyloxycarbonyl group, the benzyloxycarbonyl group, and the9-flurorenylmethyloxycarbonyl group are preferred.

(P-3) Cyclic Protective Group

In the case in which R_(A) ^(1a) and R_(A) ^(1b) bind to each other torepresent a cyclic protective group forming a ring together with anitrogen atom of the amino group, as the cyclic protective group, anN-phthaloyl group, an N-tetrachlorophthaloyl group, anN-4-nitrophthaloyl group, an N-dithiasucciloyl group, anN-2,3-diphenylmaleoyl group, an N-2,5-dimethylpyrrolyl group, anN-2,5-bis(triisopropylsiloxy)pyrrolyl group, anN-1,1,3,3-tetramethyl-1,3-disilaisoindolyl group, a3,5-dinitro-4-pyridonyl group, a 1,3,5-dioxazinyl group, and a2,2,5,5-tetramethyl-2,5-disila-1-azacyclopentane are included, althoughthis is not limited thereto. Among them, the N-phthaloyl group ispreferred.

(P-4) Other Protective Groups

In the case in which R_(A) ^(1a) and/or R_(A) ^(1b) represent aprotective group other than (P-1) to (P-3), as the protective group, abenzyl group, a p-methoxybenzyl group, a p-toluenesulfonyl group, a2-nitrobenzenesulfonyl group, a (2-trimethylsilyl)ethanesulfonyl group,an allyl group, a pivaloyl group, a methoxymethyl group, adi(4-methoxyphenyl)methyl group, a 5-dibenzosuberyl group, atrinylmethyl group, a (4-methoxyphenyl)diphenylmethyl group, a9-phenylfluorenyl group, a [2-(trimethylsilyl)ethoxy]methyl group, andan N-3-acetoxypropyl group are included, although this is not limited tothe protective groups. Preferably, a protective group that isdeprotectable without using a heavy metal catalyst may appropriately beselected for use. Among others, the benzyl group, the p-toluenesulfonylgroup, the 2-nitrobenzenesulfonyl group, and the allyl group arepreferable.

In the general formulas (I), (I-1), (II), and (III), R_(A) ² representsa linear divalent hydrocarbon group having 1 to 6 carbon atoms, or abranched or cyclic divalent hydrocarbon group having 3 to 6 carbonatoms. Specific examples of R_(A) ² include a group obtained byeliminating one hydrogen atom from each of a methyl group, an ethylgroup, an n-propyl group, an isopropyl group, an n-butyl group, anisobutyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group,a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and acyclohexyl group.

In the general formulas (I), (I-1), (II), and (III), R_(A) ³ representsa single bond, or a linear divalent hydrocarbon group having 1 to 20carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 20 carbon atoms, and the hydrocarbon group may contain a heteroatomsuch as a nitrogen atom, an oxygen atom, and a sulfur atom. Specificexamples of R_(A) ³ include a group obtained by eliminating one hydrogenatom from each of a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, an isobutyl group, a tert-butylgroup, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexylgroup, an octyl group, a decyl group, a dodecyl group, a phenyl group,an o-tolyl group, an m-tolyl group, ap-tolyl group, a 2,3-xylyl group, a2,4-xylyl group, a 2,5-xylyl group, a 2,6-xylyl group, a 3,4-xylylgroup, a 3,5-xylyl group, a mesityl group. Some of the carbon atoms inthese hydrocarbon groups may be substituted by a heteroatom such as anitrogen atom, an oxygen atom, and a sulfur atom (however, excluding: abonding site with the oxygen atom that constitutes O⁻M⁺ in the generalformula (I); and bonding site with the oxygen atom that constitutes(OR_(A) ⁵) in the general formulas (I-1), (II), and (III)). Amongothers, R_(A) ³ is preferably a structure represented by the followinggeneral formula (VII). The reason is because the compatibility betweenthe polymerization initiator represented by the general formula (I) andpolymerization solvents can be improved.—(OR_(A) ⁵)_(p) ⁻  (VII)

In the general formula (VII), R_(A) ⁵ is the same as R_(A) ⁵ in thegeneral formulas (I-1), (I-2), (II), and (III), the specific examplesthereof are as will be described later. p represents an integer of 1 to10, preferably an integer of 1 to 5, more preferably an integer of 1 to2 in the viewpoint of purifying the alcohol compound to be a rawmaterial of a polymerization initiator by distillation.

The total number of carbon atoms of R_(A) ² and carbon atoms of R_(A) ³is 4 or more. In the case in which part of the carbon atoms in R_(A) ³is substituted by a heteroatom, the total number of carbon atoms inwhich the number of heteroatoms is included as the number of carbonatoms may be 4 or more. The total number of carbon atoms of R_(A) ² andR_(A) ³ is preferably 4 to 15, more preferably 4 to 9. In thepolymerization initiator represented by the general formula (I), thelength of a chain consisting of R_(A) ² and R_(A) ³ and connecting thenitrogen atom at one end and the oxygen atom-(oxygen atom thatconstitutes O⁻M⁺) at the other end is made long, as long as 4 or more,so that the solubility to polymerization solvents is improved and, in asubstrate having a possibility that a protective group on nitrogen isrearranged on oxygen in the compound represented by the general formula(I), the rearrangement can be prevented.

In the general formulas (I-2), (II), and (III), R_(A) ⁴ represents ahydrogen atom, or a linear, branched, or cyclic hydrocarbon group thatmay be substituted, the hydrocarbon group having 1 to 12 carbon atoms,and the hydrocarbon group may contain a heteroatom. Specific examples ofR_(A) ⁴ include a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, an isobutyl group, a tert-butylgroup, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexylgroup, an octyl group, a decyl group, a dodecyl group, a phenyl group,an o-tolyl group, an m-tolyl group, ap-tolyl group, a 2,3-xylyl group, a2,4-xylyl group, a 2,5-xylyl group, a 2,6-xylyl group, a 3,4-xylylgroup, a 3,5-xylyl group, a mesityl group, a vinyl group, and an allylgroup. In the case in which R_(A) ⁴ has a substituent, examples of thesubstituent include an acetalized formyl group, a cyano group, a formylgroup, a carboxyl group, an amino group, an alkoxycarbonyl group having1 to 6 carbon atoms, an acylamide group having 2 to 7 carbon atoms,tri(same or different alkyl having 1 to 6 carbon atoms)siloxy group, asiloxy group, a silylamino group, a maleimide group, a thiol group, ahydroxide group, a methacryloyloxy group, an acryloyloxy group, anactive ester group, and an azi group. Specific examples of R_(A) ⁴having a substituent include substituents represented by the followingstructures, although this is not limited thereto. In addition, thefollowing formulas each represent an end portion of R_(A) ⁴ of asubstituted structure, and the dotted lines in the formulas show that ahydrocarbon portion of R_(A) ⁴ can have variations as exemplified above.The number of substituents is preferably 1 to 3, although this is notparticularly limited thereto. Such substituents may further be protectedby a freely selected appropriate protective group.

In the general formulas (I-1), (I-2), (II), and (III), R_(A) ⁵represents an alkylene group having 2 to 8 carbon atoms. Among others,alkylene groups having 2 to 3 carbon atoms are preferred. That is tosay, R_(A) ⁵ is preferably an ethylene group or a propylene group. The(OR_(A) ⁵) unit in the general formulas (I-1), (I-2), (II), and (III)may be constituted from a single kind of oxyalkylene group, for example,from only an oxyethylene or oxypropylene group, or two or more kinds ofoxyalkylene groups may be mixed together. In the case in which two ormore kinds of oxyalkylene groups are mixed together, (OR_(A) ⁵) may beconstituted from two or more kinds of different oxyalkylene groups byrandom polymerization or block polymerization.

In the general formulas (I) and (I-1), M represents an alkali metal.Specific examples of M include lithium, sodium, potassium, cesium,sodium-potassium alloy.

In the general formula (I-1), r represents an integer of, for example, 1to 445, preferably an integer of 10 to 395, more preferably an integerof 20 to 345.

In the general formula (I-2), k represents an integer of, for example, 0to 5. The compound represented by the general formula (I-2) where k=0has a low boiling point and is difficult to handle, or has a hightoxicity in some cases, and therefore k is preferably an integer of 1 to5, more preferably an integer of 1 to 3.

In the general formula (I-2), L represents a leaving group. Specificexamples of L include Cl, Br, I, trifluoromethanesulfonate (hereinafter,written as “TfO”), p-toluenesulfonate (hereinafter, written as “TsO”),and methanesulfonate (hereinafter, written as “MsO”), although this isnot limited thereto.

In the general formulas (II) and (III), n represents an integer of 1 to450, preferably an integer of 10 to 400, more preferably an integer of20 to 350. Moreover, n is also represented by the sum of r and k.

In selecting each of the compounds for use in each step in theproduction method of the present embodiment 1 and represented by thegeneral formulas (I), (I-1), (I-2), and (II), desired R_(A) ^(1a), R_(A)^(1b), R_(A) ², R_(A) ³, R_(A) ⁴, R_(A) ⁵, M, r, k, L, and n in thegeneral formulas (I), (I-1), (I-2), and (II) may be selected so that thecompounds represented by the general formulas (III) as the desired finalproducts may be obtained.

Moreover, the present embodiment 1 may include, as an optional stepprior to the steps a) to c), a pre-step for synthesizing the compoundrepresented by the general formula (I) used as a polymerizationinitiator. The pre-step includes: a step (pre-step 1) of synthesizing acompound represented by the following general formula (i) used as aprecursor of the polymerization initiator and; and a step (pre-step 2)of synthesizing, using the compound represented by the general formula(i), the compound represented by the general formula (I) used as apolymerization initiator. The present embodiment includes: an aspect inwhich the pre-step 2 is performed subsequently to the pre-step 1; and anaspect in which only the pre-step 2 is performed not through thepre-step 1. A scheme of the pre-step 2 is shown as follows.

(In the general formula (i), R_(A) ^(1a), R_(A) ^(1b), R_(A) ², R_(A) ³,and M are the same as defined in the general formula (I))

Moreover, the present embodiment 1 may include, as an optional stepafter the steps a) to c), a post-treatment step of purifying thecompound represented by the general formula (III) obtained in the stepc).

The preferred embodiments will be described below in the order of thepre-steps 1 to 2, the steps a) to c), and the post-treatment step alongtime series.

[Pre-Step 1]

The pre-step 1 is a step of synthesizing the alcohol compoundrepresented by the general formula (i) used as a precursor of thepolymerization initiator, and the production may be performed by thefollowing step (i-1), although this is not limited thereto.

(In the general formulas (ia) and (ib), R_(A) ^(1a), R_(A) ^(1b), R_(A)², and R_(A) ³ are the same as defined in the general formula (i),namely are the same as defined in the general formula (I), and L¹represents a leaving group)

Specific examples of L¹ as the leaving group in the general formulas(ia) and (ib) include Cl, Br, I, TfO, TsO, and MsO, although this is notlimited thereto.

In synthesizing the compound represented by the general formula (i) byperforming the step (i-1), for example, reaction may be performed byadding a basic compound to the compound represented by the generalformula (ia) without a solvent, and subsequently dripping the compoundrepresented by the general formula (ib) to mix, or, reaction may beperformed by dissolving the compound represented by the general formula(ia) in a proper solvent, then adding a basic compound, and thendripping the compound represented by the general formula (ib) to mix.The amount of the compound represented by the general formula (ib) usedis, for example, 1 to 5 times, preferably 1.5 to 3 times the number ofmoles of the compound represented by the general formula (ia), and, inthe viewpoint of reacting a protective group selectively with only anamino group, 1.5 to 2 times are more preferred.

In the case in which a solvent is used in the step (i-1), and specificexamples of the solvent include ethers such as THF and 1,4-dioxane,aromatic hydrocarbons such as benzene, toluene, and xylene, halogenssuch as methylene chloride, and N,N-dimethylformamide,N-methyl-2-pyrrolidone, acetonitrile, and acetone, although this is notlimited thereto. The amount of the solvent used is, for example, 1 to 20times, preferably 2 to 10 times, more preferably 2 to 5 times the massof the compound represented by the general formula (ia), although thisis not particularly limited thereto.

Specific examples of the basic compound for use in the step (i-1)include hydroxides such as sodium hydroxide, potassium hydroxide, andtetramethylammonium hydroxide, carbonates such as sodium carbonate,potassium carbonate, and cesium carbonate, metal alkoxides such assodium methoxide, sodium ethoxide, and potassium t-butoxide, metalhydrides such as sodium hydride and potassium hydride, and primary,secondary, and tertiary aliphatic amines, conjugated amines, aromaticamines, heterocyclic amines, and ammonia water, although this is notlimited thereto. The amount of the basic compound used is, for example,1 to 5 times, preferably 1.5 to 3 times, more preferably 1.5 to 2 timesthe mass of the compound represented by the general formula (ia).

The reaction temperature in the step (i-1) may be within a range fromthe melting point to the boiling point of the solvent used, and is, forexample, −60° C. to 150° C., preferably 0° C. to 80° C. The completionof the reaction in the step (i-1) can be assumed when the compoundrepresented by the general formula (ia) analyzed by gas chromatographydisappears, or when the compound represented by the general formula (i)is obtained as a main product.

In the case in which R_(A) ^(1a) and R_(A) ^(1b) are intended to bedifferent protective groups, or in the case in which there is a riskthat a protective group protects not only an amino group but also ahydroxy group because of a high steric hindrance of the protectivegroup, synthesis may be performed by protecting an amino group by afirst protective group in the first place, then protecting a hydroxygroup by another deprotectable protective group, subsequently protectingthe amino group further by a second protective group, and finallydeprotecting the hydroxy group. It can happen that a protective groupmay protect a hydroxy group, or only one protective group is introducedin an amino group because selectivity of the amino group against ahydroxy group is not obtained depending on the reaction condition,however, in that case, the compound represented by the general formula(i) and the other by-products can be separated by precisiondistillation. The compound represented by the general formula (i) ispreferably purified by distillation to remove water, even in the case inwhich the by-product is not produced. In that case, the water contentratio of the compound represented by the general formula (i) is, forexample, 50 ppm or less, preferably 10 ppm or less, more preferably 5ppm or less.

In the case in which R_(A) ³ in the compound represented by the generalformula (i) contains a heteroatom, examples of the other methods forproducing the compound represented by the general formula (i) includesuch, methods as (i-2) to (i-3) using a compound represented by thegeneral formula (if) having a hydrogen atom next to the heteroatom,although this is not limited thereto.

(In the general formulas (ic), (id), (ie), and (if), R_(A) ^(1a), R_(A)^(1b), R_(A) ², R_(A) ³, and L¹ are the same as defined in the generalformulas (ia) and (ib), and L² represents a leaving group)

Specific examples of L² as the leaving group in the general formulas(ic) and (ie) include Cl, Br, I, TfO, TsO, and MsO, although this is notlimited thereto.

In performing the step (i-2), for example, reaction may be performed byadding a basic compound to the compound represented by the generalformula (ic) without a solvent, and subsequently dripping the compoundrepresented by the general formula (id) to mix, or, reaction may beperformed by dissolving the compound represented by the general formula(ic) in a proper solvent, then adding a basic compound, and thendripping the compound represented by the general formula (id) to mix.The amount of the compound represented by the general formula (id) usedis, for example, 2 to 10 times, preferably 2 to 5 times, more preferably2 to 3 times the number of moles of the compound represented by thegeneral formula (ic).

In the case in which a solvent is used in the step (i-2), specificexamples of the solvent are the same as the specific examples of thesolvent described in the step (i-1). The amount of the solvent used is,for example, 1 to 20 times, preferably 2 to 10 times, more preferably 2to 5 times the mass of the compound represented by the general formula(ic), although this is not particularly limited thereto.

Specific examples of the basic compound for use in the step (i-2) arethe same as the specific examples of the basic compound described in thestep (i-1). The amount of the basic compound used is, for example, 2 to10 times, preferably 2 to 5 times, more preferably 2 to 3 times thenumber of moles of the compound represented by the general formula (ic).

The reaction temperature in the step (i-2) may be within a range fromthe melting point to the boiling point of the solvent used, and is, forexample, −60° C. to 150° C., preferably 0° C. to 80° C. The completionof the reaction in the step (i-2) can be assumed when the compoundrepresented by the general formula (ic) analyzed by gas chromatographydisappears, or when the compound represented by the general formula (ie)is obtained as a main product.

In synthesizing the compound represented by the general formula (i) bysubsequently performing the step (i-3), the compound represented by thegeneral formula (if) and a basic compound may be directly added to thereaction liquid after completion of the step (i-2), or, the compoundrepresented by the general formula (ie) may be dripped into a mixedsolution of the compound represented by the general formula (if), thebasic compound, and the solvent, after the compound represented by thegeneral formula (ie) is once purified and extracted. Moreover, the step(i-3) may be performed without a solvent. The amount of the compoundrepresented by the general formula (if) used is 1 to 30 times,preferably 2 to 20 times, more preferably 5 to 10 times the number ofmoles of the compound represented by the general formula (ie). Forexample, in the case in which R_(A) ³ is a compound represented by thegeneral formula (VII), the compound represented by the general formula(if) is a diol, and use of the compound represented by the generalformula (if) in an excessive amount relative to the number of moles ofthe compound represented by the general formula (ie) makes it possibleto react a hydroxy group at one end of the compound represented by thegeneral formula (if).

In the case in which a solvent is used in the step (i-3), and specificexamples of the solvent are the same as the specific examples of thesolvent described in the step (i-1). The amount of the solvent is, forexample, 1 to 20 times, preferably 2 to 10 times, more preferably 2 to 5times the mass of the compound represented by the general formula (ie),although this is not particularly limited thereto. Specific examples ofthe basic compound for use in the step (i-3) are the same as thespecific examples of the basic compound described in the step (i-1). Theamount of the basic compound used is, for example, 1 to 2 times,preferably 1 to 1.5 times, more preferably 1 to 1.2 times the number ofmoles of the compound represented by the general formula (ie).

The reaction temperature in the step (i-3) may be within a range fromthe melting point to the boiling point of the solvent, and is, forexample, −60° C. to 150° C., preferably 0° C. to 80° C. The completionof the reaction in the step (i-3) can be assumed when the compoundrepresented by the general formula (ie) analyzed by gas chromatographydisappears. Both the heteroatom on R_(A) ³ and the hydroxy group at anend react with the compound represented by the general formula (ie) toproduce a by-product in some cases depending on the reaction condition;however, in that case, the compound represented by the general formula(i) and by-product can be separated by precision distillation. Thecompound represented by the general formula (i) is preferably purifiedby distillation to remove water, even in the case in which theby-product is not produced. In that case, the water content ratio of thecompound represented by the general formula (i) is, for example, 50 ppmor less, preferably 10 ppm or less, more preferably 5 ppm or less.

[Pre-Step 2]

The pre-step 2 is a step of reacting the compound represented by thegeneral formula (i) with an alkali metal or an alkali metal compound toobtain the compound represented by the general formula (I).

In the [Pre-Step 2], the alkali metal or the alkali metal compound to bereacted with the compound represented by the general formula (i) may bea substance selected from the group consisting of alkali metalsrepresented by M, hydrides of alkali metals represented by M⁺H⁻, organicalkali metals represented by R_(X) ⁻M⁺ or [R_(Y)]⁻ (R_(X) represents analkyl group that may have a substituent, the alkyl group having 1 or 20carbon atoms, preferably represents an alkyl group having 1 to 20 carbonatoms, or an arylalkyl group having 7 to 20 carbon atoms, and Ryrepresents an aromatic compound that may have a substituent), and alkalimetal salts of monohydric alcohols represented by R_(Z)O⁻M⁺ (R_(Z)represents an alkyl group having 1 to 6 carbon atoms).

Specific examples of M as the alkali metal include lithium, sodium,potassium, cesium, and sodium-potassium alloy. Specific examples of M⁺H⁻include sodium hydride, and potassium hydride. Specific examples ofR_(X) ⁻M⁺ include ethyllithium, ethylsodium, n-butyllithium,sec-butyllithium, tert-butyllithium, 1,1-diphenylhexyllithium,1,1-diphenyl-3-methylpentyllithium, 1,1-diphenylmethylpotassium,cumylsodium, cumylpotassium, and cumylcesium. Specific examples of[R_(Y)]^(.−)M⁺ include lithium naphthalenide, sodium naphthalenide,potassium naphthalenide, anthracenelithium, anthracenesodium,anthracenepotassium, biphenylsodium, sodium 2-phenylnaphthalenide,phenanthrenesodium, sodium acenaphthylenide, sodium benzophenone ketyl,sodium 1-methylnaphthalenide, potassium 1-methylnaphthalenide, sodium1-methoxynaphthalenide, potassium 1-methoxynaphthalenide, and thesecompounds may be used alone or in combination of two or more. Specificexamples of R_(Z) in R_(Z)O⁻M⁺ include a methyl group, an ethyl group,an n-propyl group, an isopropyl group, an n-butyl group, a sec-butylgroup, a tert-butyl group, an n-pentyl group, an isopentyl group, and ann-hexyl group, although this is not limited thereto. Among others, asalkali metal or the alkali metal compound, sodium, potassium, sodiumhydride, and potassium hydride are preferred in the view point that sidereaction is suppressed, and moreover, sodium naphthalenide, potassiumnaphthalenide, anthracenesodium, anthracenepotassium, sodium methoxide,potassium methoxide, sodium ethoxide, and potassium ethoxide arepreferred in the viewpoint of high reactivity.

The amount of the alkali metal or the alkali metal compound used in thereaction in the pre-step 2 is 0.5 to 3.0 equivalents, preferably 0.8 to2.0 equivalents, more preferably 0.9 to 1.0 equivalents, relative to thenumber of moles of the compound represented by the general formula (i).Particularly in the case in which the alkali metal compound that canalso function as a polymerization initiator is used in the step a), itis necessary to suppress the amount of the alkali metal compound used to1.0 equivalent or less. For example, in the case in which potassiummethoxide is used, it is necessary to distill away methanol produced inthe pre-step 2 under reduced pressure after synthesis of thepolymerization initiator so that potassium methoxide may not function asa polymerization initiator in the step a).

In synthesizing the compound represented by the general formula (I) inthe pre-step 2, for example, the alkali metal or the alkali metalcompound may be directly added after the compound represented by thegeneral formula (i) distilled and purified in the pre-step 1 isdissolved in a proper solvent, or, the compound represented by thegeneral formula (i) may be added to a solution obtained by dissolvingthe alkali metal or the alkali metal compound in a proper solvent.Specific examples of the solvent used in the pre-step 2 include etherssuch as THF and 1,4-dioxane, and aromatic hydrocarbons such as benzene,toluene, and xylene, although this is not limited thereto. In the casein which the solvent is used, a solvent distilled with a dehydratingagent such as metal sodium is preferably used. The water content ratioof the solvent is, for example, 50 ppm or less, preferably 10 ppm orless, more preferably 5 ppm or less. The amount of the solvent used is,for example, 1 to 50 times, preferably 2 to 10 times, more preferably 2to 5 times the mass of the compound represented by the general formula(i), although this is not particularly limited thereto. Moreover, thereaction in the pre-step 2 is performed at a temperature of −78 to 100°C., preferably at a temperature of 0° C. to the reflux temperature ofthe solvent for use (for example, 0° C. to 66° C. as a refluxtemperature of THF), and the reaction system may be cooled or heated asneeded.

Among others, as the solvent for use in the [Pre-Step 2], the samesolvent as will be used as the polymerization solvent in the subsequent[Step a] as will be described later is preferably used. The reason isbecause whether the polymerization initiator synthesized in the[Pre-Step 2] dissolves or not in the polymerization solvent for use inthe [Step a] can be confirmed in advance during the synthesis of thepolymerization initiator in the [Pre-Step 2]. Specifically, thesolubility of the polymerization initiator in the polymerization solventcan be confirmed in a manner as described below in the case in which,for example, THF is used as the reaction solvent in the [Pre-Step 2],potassium hydride (for example, 1.0 equivalent or less of potassiumhydride relative to the compound represented by the general formula (i))is used as the alkali metal compound, and THF is used as thepolymerization solvent in the [Step a]. As the reaction in the [Pre-Step2] progresses, potassium hydride in a powder form decreases and hydrogenis produced. By confirming whether the precipitation of a salt and thecloudiness in the reaction solution are observed or not when all of thepotassium hydride is finally reacted without the precipitation of thepolymerization initiator represented by the general formula (I) in THF,the solubility of the polymerization initiator in the polymerizationsolvent in the subsequent [Step a] can be confirmed in advance.

Moreover, as another method for confirming the solubility of thepolymerization initiator represented by the general formula (I) in thepolymerization solvent for use in the [Step a], the method as describedbelow can be given as an example, although this is not limited thereto.As described above, the compound represented by the general formula (i)is reacted with the alkali metal or the alkali metal compound tosynthesize the polymerization initiator represented by the generalformula (I), and then the solvent and the reagents other than thepolymerization initiator represented by the general formula (I) areremoved by a usual method to extract the polymerization initiatorrepresented by the general formula (I). The obtained polymerizationinitiator represented by the general formula (I) is dissolved in thepolymerization solvent to be used in the subsequent [Step a] at aconcentration of, for example, 20 wt. %, and whether the precipitationof a salt and the cloudiness are observed or not can be confirmed byvisual observation.

As described above, the polymerization of an alkylene oxide with apolymerization initiator prepared with a water-containing monohydricalcohol that is a polymerization initiator raw material produces a diolpolymer as by-product. Separation of a diol polymer from the targetsubstance is extremely difficult, and it is likely that the intendedperformance of a polymer micellizing agent cannot be achieved with thedirect use of the polymer which contains a diol polymer or impuritiesderived therefrom. Therefore, in the polymerization reaction in thesubsequent [Step a], the water content in the reaction system comprisingthe compound (polymerization initiator) represented by the generalformula (I) is dissolved is preferably reduced to be as low as possible.Regarding this, a compound represented by the general formula (i) with,for example, R_(A) ^(1a)=R_(A) ^(1b)=a triethylsilyl group, R_(A)²=CH₂CH₂ CH₂, R_(A) ³═O CH₂CH₂, and a high boiling point of 120° C. (10Pa), the compound being a precursor of the compound represented by thegeneral formula (I), has a sufficient difference in boiling point fromwater, so that separation of water can be achieved by drying underreduced pressure. Therefore, it is preferred that, prior to the reactionof the compound represented by the general formula (i) with the alkalimetal or the alkali metal compound in the [Pre-Step 2], the compoundrepresented by the general formula (i) is sufficiently dried underreduced pressure and then distilled. In that case, the water contentratio of the compound represented by the general formula (i) afterdistillation is reduced, for example, to 50 ppm or less, preferably 10ppm or less, more preferably 5 ppm or less. In this way, by reducing thewater content of the compound represented by the general formula (i)that is a raw material of the polymer initiator to be as low aspossible, by-production of the diol polymer can more favorably besuppressed in performing polymerization using the obtainedpolymerization initiator.

The concentration of a substance (mmol/g) that can function as apolymerization initiator in a reaction solution after completion of the[Pre-Step 2] (reaction solution after synthesis of the polymerizationinitiator) can be determined from the amount of substance of the rawmaterial alcohol represented by the general formula (i) for use in the[Pre-Step 2] and the total weight of the reaction solution aftercompletion of the [Pre-Step 2]. That is to say, the concentration of thesubstance that can function as the polymerization initiator in thereaction solution after completion of the [Pre-Step 2] can be determinedby “amount of substance of raw material alcohol (i) used (mmol)/totalweight of reaction solution (g) after completion of [Pre-Step 2]”. Thereason is because the raw material alcohol also functions as thepolymerization initiator in the case in which the raw material alcoholrepresented by the general formula (i) is left in the reaction solutionafter completion of the [Pre-Step 2]. The reaction in the subsequent[Step a] is an equilibrium reaction, and therefore, the compoundrepresented by the general formula (I) reacts as the polymerizationinitiator to produce a polymer, and an alkoxide at an end of the polymereliminates a proton of the raw material alcohol (i) to allow the rawmaterial alcohol to function as an alkoxide (polymerization initiator).However, as will be described later, the residual amount of the rawmaterial alcohol in the reaction solution after completion of the[Pre-Step 2] is preferably as small as possible. The reaction solutionafter completion of the [Pre-Step 2] may be used as it is as apolymerization initiator solution in the subsequent [Step a].

Conventionally, sodium salts and potassium salts that are generally usedpolymerization initiators do not dissolve in polymerization solventssuch as THF in many cases. In that case, in order to uniformly performpolymerization, an excessive amount of alcohol that is a initiator rawmaterial has to be left (for example, in Japanese Patent No. 3050228, 13mol of methanol to 2 mol of sodium methoxide that is a polymerizationinitiator). However, due to the presence of these alcohols in a reactionsystem, reduction in the polymerization rate is unavoidable.Consequently, crucial reaction conditions such as high temperature andhigh pressure are required for increasing the polymerization rate. Incontrast, the alcohol derivative: that is used as a polymerizationinitiator in the present embodiment; that is represented by the formula(I); and the amino group of which is protected by a protective grouphas, in its structure, a structure that is similar to that of thepolymerization solvent, and therefore is easily soluble to thepolymerization solvent. For example, in the case in which R_(A) ³ has anoxyethylene structure, the compound represented by the general formula(I) is easily soluble to ether compounds including THF and diethyleneglycol dimethyl ether. Therefore, the raw material alcohol does not haveto be left in order to dissolve a polymerization initiator in apolymerization solvent. Therefore, the polymerization rate is increased,and polymerization under mild conditions is possible.

In this way, in order to obtain a sufficient reaction rate under mildconditions in the subsequent step a), a polymerization initiator havinga small amount of a residual alcohol is preferably synthesized in thepre-step 2. Specifically, the ratio of the amounts of substances betweenthe polymerization initiator represented by the general formula (I) andthe initiator alcohol raw material represented by the general formula(i) is preferably 100:0 to 80:20 (mol %) after synthesis of thepolymerization initiator represented by the general formula (I) from thealcohol as an initiator raw material represented by the general formula(i), and more preferably reaction is performed so that the ratio is100:0 to 90:10 (mol %). In order to achieve that, the [Pre-Step 2] ispreferably performed under the condition so that the number of moles ofthe alkali metal or the alkali metal compound used is 0.8 to 1.5,preferably 0.9 to 1.0 times the number of moles of the compound used andrepresented by the general formula (i).

It is also possible to distill away the alcohol as an initiator rawmaterial represented by the general formula (i) under reduced pressureafter synthesis of the polymerization initiator represented by thegeneral formula (I). In that case, the raw material alcohol ispreferably removed until the ratio of the amounts of substances betweenthe polymerization initiator represented by the general formula (I) andthe alcohol as an initiator raw material represented by the generalformula (i) is 100:0 to 98:2 (mol %) after completion of the [Pre-Step2], and more preferably the raw material alcohol is removed until theratio is 100:0 to 99:1 (mol %). By reducing the amount of the residualraw material alcohol, it is possible to increase the polymerization ratein the subsequent [Step a] more.

In the present embodiment, as described above, even when the alcoholcompound represented by the general formula (i), that is an initiatorraw material and that is a factor of increasing the solubility of thepolymerization initiator in polymerization solvents, and, on the otherhand, also a factor of reducing the polymerization rate, is not left, itis possible to dissolve the compound represented by the general formula(I) as a polymerization initiator in polymerization solvents. Astructure that plays the role is R_(A) ³ in the general formula (I),and, for example, in the case in which the polymerization solvent isTHF, the compatibility between the polymerization initiator and thepolymerization solvent is enhanced preferably by preparing R_(A) ³ so asto have a structure as represented by the general formula (VII) ((OR_(A)⁵)_(p)), making it possible to dissolve the polymerization initiator inthe polymerization solvent without a substantial presence of the rawmaterial alcohol. As a result thereof, polymerization in a uniformsystem becomes possible, and synthesizing of a narrowly distributedpolyalkylene glycol derivative under mild conditions becomes possible.

[Step a)]

The step a) is a step of reacting the compound represented by thegeneral formula

(I) (polymerization initiator) with an alkylene oxide in apolymerization solvent. According to the step a), the compoundrepresented by the following general formula (I-1) can be obtained.

In the [Step a], the compound represented by the general formula (I) isreacted with an alkylene oxide after the compound represented by thegeneral formula (I) is completely dissolved in the polymerizationsolvent. As described above, the compound represented by the generalformula (I) is easily soluble to the polymerization solvent even whenthe compound represented by the general formula (i) that is the rawmaterial alcohol is not substantially present. Among others, R_(A) ³ inthe general formula (I) preferably has the alkylene oxide structurerepresented by the general formula (VII) (—(OR_(A) ⁵)_(p)—) in theviewpoint of high compatibility with polymerization solvents. That thecompound represented by the general formula (I) can completely bedissolved in the polymerization solvent can be confirmed by, forexample, the fact that the precipitation of a salt or cloudiness is notobserved in the polymerization solvent by visual observation. In thiscase, the precipitation of a salt and the cloudiness are not desirablyobserved in a state in which the mass of the polymerization solvent isequal to or less than 10 times (and equal to or less than 1 times) themass of the compound represented by the general formula (I). That is tosay, the precipitation of a salt and the cloudiness are not desirablyobserved in a state in which the concentration of the compoundrepresented by the general formula (I) in the polymerization solventsolution is 9.1 wt. % or more (and 50 wt. % or less). After confirmingas described above, the polymerization solvent solution containing thecompound represented by the general formula (I) may be used forpolymerization reaction keeping the concentration as it is during theconfirmation, or may be used for polymerization reaction in a dilutedstate by further adding the polymerization solvent. In addition, theamount of the polymerization solvent may be adjusted so as to be, forexample, 1 to 50 times, preferably 2 to 25 times the mass of thealkylene oxide used at the time of starting the polymerization reaction.

Furthermore, as described above, the presence of the raw materialalcohol becomes the factor of reducing the polymerization rate, andtherefore the polymerization initiator is preferably used in a state inwhich the amount of the raw material alcohol is small in the [Step a].For example, in the case in which the pre-step 2 is performed prior tothe step a), the reaction product obtained in the pre-step 2 andcontaining the polymerization initiator represented by the generalformula (I) and the raw material alcohol represented by the generalformula (i), preferably in a ratio of the amounts of substances of 100:0to 80:20 (the reaction product containing a small amount of the rawmaterial alcohol), is preferably used by directly dissolving thereaction product in a polymerization solvent

As the polymerization solvent for use in the [Step a], cyclic ethercompounds having 4 to 10 carbon atoms or linear or branched ethercompounds are preferably used in the viewpoint that compatibility withthe polymerization initiator is high. Specific examples of the cyclicether compound includes furan, 2,3-dihydrofuran, 2,5-dihydrofuran,2,3-dimethylfuran, 2,5-dimethylfuran, tetrahydrofuran (THF),2-methyltetrahydrofuran, 3-methyltetrahydrofuran,2,5-dimethyltetrahydrofuran, 1,2-methylenedioxybenzene, 1,3-dioxolane,2-methyl-1,3-dioxolane, 4-methyl-1,3-dioxolane,2,2-dimethyl-1,3-dioxolane, 3,4-dihydro-2H-pyran, tetrahydropyran,1,3-dioxane, 1,4-dioxane, 2,4-dimethyl-1,3-dioxane, 1,4-benzodioxane,1,3,5-trioxane, and oxepane, although this is not limited thereto.Specific example of the linear or branched ether compound includemonoethylene glycol dimethyl ether, diethylene glycol dimethyl ether,and triethylene glycol dimethyl ether, although this is not limitedthereto. THF in particular is preferably used. Moreover, polymerizationsolvents other than the ether compounds may be used, and specificexamples thereof include aromatic hydrocarbons such as benzene, toluene,and xylene, although this is not limited thereto. The polymerizationsolvent for use may be a single solvent, or may be used in combinationof two or more. In the case in which the polymerization solvents areused in combination, the combination and the mixing ratio is notparticularly limited.

The amount of the polymerization solvent used for polymerizationreaction is, for example, 1 to 50 times, preferably 2 to 30 times, morepreferably 3 to 20 times the mass of the alkylene oxide used, althoughthis is not particularly limited. The polymerization solvent distilledwith, for example, a dehydrating agent such as metal sodium ispreferably used. The water content of the polymerization solvent is, forexample, 50 ppm or less, preferably 10 ppm or less, more preferably 5ppm or less.

Specific example of the alkylene oxide used includes ethylene oxide,propylene oxide. Among them, ethylene oxide is preferred in theviewpoint of high polymerizability. The ratio of amounts of use betweenthe compound used for polymerization reaction and represented by thegeneral formula (I) and the alkylene oxide is, for example, 1:1 to1:450, preferably 1:10 to 1:400 as the ratio of the amounts ofsubstances of the compound represented by the general formula (I): thealkylene oxide, although this is not particularly limited thereto.

In the step a), for example, the alkylene oxide may be added in onebatch to a reaction system with the compound represented by the generalformula (I) dissolved in the polymerization solvent, or the alkyleneoxide may successively be added to the reaction system. Or, a solutionof the alkylene oxide dissolved in the polymerization solvent may bedripped into the reaction system. The polymerization may be performed ata temperature of, for example, 30 to 80° C., preferably 50 to 80° C.,more preferably 60 to 80° C. The pressure during polymerization is, forexample, 1.0 MPa or less, preferably 0.5 MPa or less. The degree ofprogress of polymerization reaction can be monitored with GPC, and whenno change is observed in conversion ratio of the alkylene oxide, thecompletion can be assumed. As described above, the present embodiment isadvantageous in that crucial reaction conditions such as hightemperature and high pressure are not required in polymerization.

[Step b)]

The step b) is a step of reacting the compound represented by thegeneral formula (I-1) obtained in the step a) with the compoundrepresented by the following general formula (I-2). Through the step b),the compound represented by the following general formula (II) can beobtained.R_(A) ⁴(OR_(A) ⁵)_(k)L  (I-2)

In synthesizing the compound represented by the general formula (II) inthe step b), for example, the compound represented by the generalformula (I-2) may directly be added to the reaction liquid (reactionliquid containing (I-1)) after completion of the reaction in step a), orthe compound represented by the general formula (I-2) may be dissolvedfor use in a proper solvent as needed. Specific examples of the solventused include ethers such as THF and 1,4-dioxane, and aromatichydrocarbons such as benzene, toluene, and xylene. The amount of thesolvent used is, for example, 1 to 50 times, preferably 2 to 10 times,more preferably 2 to 5 times the mass of the compound represented by thegeneral formula (I-2), although this is not particularly limitedthereto. The reaction may be performed at a temperature of, for example,0 to 100° C., preferably at a temperature of 40 to 70° C., and thereaction system may be cooled or heated as needed. The amount of thecompound represented by the general formula (I-2) used is, for example,1 to 50 equivalents, preferably 1 to 40 equivalents, more preferably 1to 30 equivalents, relative to the number of moles of the compoundrepresented by the general formula (I-1). The degree of progress ofreaction can be monitored with ¹H-NMR, and when a peak derived from ahydroxy group produced in quenching the reaction liquid with waterdisappears, the completion can be assumed.

Although the reaction in the step b) proceeds without a catalyst, abasic catalyst may be added for further acceleration of the reaction. Asthe basic catalyst, hydroxides such as sodium hydroxide, potassiumhydroxide, and tetramethylammonium hydroxide, carbonates such as sodiumcarbonate, potassium carbonate, and cesium carbonate, metal alkoxidessuch as sodium methoxide, sodium ethoxide, and potassium t-butoxide,metal hydrates such as sodium hydrate and potassium hydrate, andprimary, secondary, and tertiary aliphatic amines, conjugated amines,aromatic amines, heterocyclic amines, and ammonia water may be used,although this is not limited thereto. The amount of the basic catalystused is, for example, 0.1 to 30 times, preferably 1 to 20 times thenumber of moles of the compound represented by the general formula(I-1).

In the step b), an alkaline adsorbent may further be used in order toseparate an alkali metal salt produced through the reaction of thecompound represented by the general foimula (I-1) with the compoundrepresented by the general formula (I-2). As the suitable alkaliadsorbent, an aluminum hydroxide (e.g. “KYOWADO 200” made by KyowaChemical Industry Co., Ltd.), a synthesized hydrotalcite (e.g. “KYOWADO500” made by Kyowa Chemical Industry Co., Ltd.), a synthesized magnesiumsilicate (e.g. “KYOWADO 600” made by Kyowa Chemical Industry Co., Ltd.),a synthesized aluminum silicate (e.g. “KYOWADO 700” made by KyowaChemical Industry Co., Ltd.), and an aluminum oxide/magnesium oxidesolid solution (e.g. “KW-2000” made by Kyowa Chemical Industry Co., Ltd.and “TOMITA AD 700NS” made by Tomita Pharmaceutical Co., Ltd.) are used,however the adsorption material is not limited thereto. Among them,KW-2000 is preferred because of high ion trapping ability. The amount ofthe alkali adsorbent used may be 0.01 to 10 times, preferably 0.1 to 8times, more preferably 0.3 to 6 times the mass of the compoundrepresented by the general formula (II), although this is notparticularly limited thereto. An alkali adsorbent may be directly fedinto the reaction liquid at the time of completion of the reaction ofthe compound represented by the general formula (I-1) with the compoundrepresented by the general formula (I-2), or may be fed into thereaction liquid after the reaction is completed and the produced alkalimetal salt is filtered. The adsorbent may be removed by filtration afterthe reaction was performed for 0.5 to 6 hours after feeding theadsorbent, however the reaction time is not particularly limited. As amethod of using the adsorption material, the adsorption material may beused as a batch system and added into the reaction solution to performstirring, or the adsorption material may be used as a column system andthe reaction solution may be allowed to pass through a column where theadsorption material is filled. Specific example of the solvent in thecase of performing adsorption treatment include ethers such as THF and1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene,esters such as ethyl acetate, n-butyl acetate, and γ-butyrolactone,ketones such as acetone, methyl ethyl ketone, and methyl isobutylketone, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), andacetonitrile, although this is not limited thereto. The aromatichydrocarbons such as benzene, toluene, and xylene are preferred for thepurpose of enhancing the ability of adsorbing salts. These solvents maybe used singly or in combinations of two or more. In that case, themixing ratio is not particularly limited.

In the case in which the compound represented by the general formula(II) is solid, the compound represented by the general formula (II) maybe extracted as solid for use before the subsequent step c). In thatcase, crystallization may be performed by dripping the reaction liquiddirectly or after concentration to a poor solvent. In concentrating thereaction liquid, the concentration of the compound represented by thegeneral formula (II) is adjusted to be, for example, 10 to 50 mass %,preferably 15 to 45 mass %, more preferably 20 to 40 mass %.

In concentrating the reaction liquid, crystallization may be performedafter solvent substitution with a good solvent of the compoundrepresented by the general formula (II). In that case, specific examplesof the good solvent include ethers such as

THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, andxylene, esters such as ethyl acetate, n-butyl acetate, andγ-butyrolactone, ketones such as acetone, methyl ethyl ketone, andmethyl isobutyl ketone, dimethyl sulfoxide (DMSO), N,N-dimethylformamide(DMF), and acetonitrile, although this is not limited thereto. Thesesolvents may be used singly or in combination of two or more. In thatcase, the mixing ratio is not particularly limited. The concentration ofthe compound represented by the general formula (II) after solventsubstitution is, for example, 5 to 50 mass %, preferably 10 to 40 mass%, more preferably 10 to 30 mass %.

The poor solvent for use has a low solubility for the compoundrepresented by the general formula (II). Examples of the suitable poorsolvent for use include hydrocarbon such as hexane, heptane, octane,nonane, decane, cyclopentane, cyclohexane, cycloheptane, andcyclooctane, and ethers such as diethyl ether, diisopropyl ether, anddi-n-butyl ether. The amount of the poor solvent used is, for example, 5to 100 times, preferably 5 to 50 times, more preferably 5 to 20 timesthe mass of a compound represented by the general formula (II), althoughthis is not particularly limited thereto. The poor solvents may be usedsingly, or the poor solvent may be mixed with a different solvent foruse. Examples of the different solvent for mixing include esters such asethyl acetate, n-butyl acetate, and γ-butyrolactone, ketones such asacetone, methyl ethyl ketone, and methyl isobutyl ketone, hydrocarbonssuch as benzene, toluene, xylene, and cumene, ethers such astetrahydrofuran, diethyl ether, and 1,4-dioxane, alcohols such asmethanol, ethanol, isopropyl alcohol, and ethylene glycol monomethylether, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), andacetonitrile, although this is not limited thereto.

In the step b), after precipitation of solid by crystallization, thesolid may be washed for purification as needed. Preferably the solventfor use in washing is the same poor solvent as described above, althoughthis is not particularly limited thereto. The amount of the washingsolvent used is also not particularly limited. The produced solid isdried under reduced pressure, so that a compound represented by thegeneral formula (II) can be extracted as solid.

In the case in which water is mixed during polymerization of an alkyleneoxide in the previous step a), a diol derivative is produced asdescribed previously, and a compound represented by the followinggeneral formula (VIII) is produced further through the step b).R_(A) ⁴(OR_(A) ⁵)_(q)OR_(A) ⁴  (VIII)(In the general formula (VIII), R_(A) ⁴ and R_(A) ⁵ are the same asdefined in the general formula (II), and q represents an integer of 1 to890)

The diol derivative represented by the general formula (VIII) isproduced in the case in which water functions as a polymerizationinitiator, and therefore the polymerization progresses from both ends,which is different from the case in which the polymerization initiatorrepresented by the general formula (I) works. Therefore, q is abouttwice r in the general formula (I-1), and represents an integer of, forexample, 1 to 890, preferably an integer of 20 to 790, more preferablyan integer of 40 to 690. In the present embodiment, the polymerizationreaction is preferably performed in a state in which the water contentin the reaction system is suppressed at a low level as described above,so that the production of the diol derivative such as described abovecan be suppressed.

Moreover, in the conventional synthesis methods described in JapanesePatent No. 3050228 and Japanese Patent No. 3562000, the polymerizationend is converted to a cyanoethyl group, and subsequently to an aminogroup, thus a diol impurity finally leads to a compound having aminogroups at both end. The compound has an end structure similar to that ofthe target compound, and therefore cannot be separated by such apurification method with a cation exchange resin as will be describedlater. In contrast, in the present embodiment, the diol derivativerepresented by the general formula (VIII) has a different end structurefrom that of the target compound represented by the general formula(III). It is therefore possible to separate the diol derivativerepresented by the general formula (VIII) by, for example, suchpurification with a cation exchange resin as will be described later,and, as a result thereof, a high-purity polyalkylene glycol derivative(III) having an amino group may be synthesized.

[Step c)]

In the step c), the protective group in the compound represented by thegeneral formula (II) obtained in the step b) is deprotected. Thedeprotection is preferably performed without using a heavy metalcatalyst. The heavy metal catalyst here is a catalyst using a heavymetal such as, for example, Co, Ni, Pd, Pt, Rh, Ru, Cu, and Cr as a rawmaterial. As a method for performing deprotection without using a heavymetal catalyst in the step c), for example, in the case in which R_(A)^(1a) and/or R_(A) ^(1b) in the general formula (II) represent a silylgroup (in the case of (P-1)), water or an alcohol (R⁶OH: wherein R⁶represents a hydrocarbon group having 1 to 5 carbon atoms) is reactedwith the compound represented by the general formula (II) in thepresence of an acid catalyst, so that conversion to the compoundrepresented by the general formula (III) may be performed. Specificexamples and the amount of the acid catalyst used are as will bedescribed later in the embodiment 2.

Moreover, in the case in which R_(A) ^(1a) and/or R_(A) ^(1b) representa tert-butyloxycarbonyl group (in the case of (P-2)) for example,deprotection may be performed by allowing a strong acid such astrifluoroacetic acid and hydrochloric acid to act on the compoundrepresented by the general formula (II). The amount of the strong acidused is, for example, 0.01 to 1000 equivalents, preferably 0.1 to 100equivalents, more preferably 1 to 10 equivalents, relative to the numberof moles of the compound represented by the general formula (II).

In the case in which R_(A) ^(1a) and R_(A) ^(1b) represent anN-phthaloyl group (in the case of (P-3)) for example, the phthaloylgroup may be eliminated by reacting a hydrazine hydrate with thecompound represented by the general formula (II) in an alcohol. Examplesof the alcohol for use include methanol, ethanol, n-propyl alcohol,isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and tert-butylalcohol. The amount of the alcohol used is, for example, 1 to 100 times,preferably 3 to 50 times, more preferably 5 to 10 times the mass of thecompound represented by the general formula (II). The amount of thehydrazine hydrate used is, for example, 1 to 50 equivalents, preferably2 to 20 equivalents, more preferably 3 to 10 equivalents, relative tothe number of moles of the compound represented by the general formula(II).

In the case in which R_(A) ^(1a) and/or R_(A) ^(1b) represent a benzylgroup or an ally group (in the case of (P-4)) for example, deprotectionof the compound represented by the general formula (II) may be performedunder the condition of Birch reduction in which liquid ammonium andmetal sodium are used. The amount of liquid ammonium used is, forexample, 1 to 100 times, preferably 3 to 50 times, more preferably 5 to10 times the mass of the compound represented by the general formula(II). The amount of metal sodium used is, for example, 2 to 50equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5equivalents, relative to the number of moles of the compound representedby the general formula (II). As in the examples above, deprotection maybe performed by appropriately selecting the condition where a heavymetal catalyst is not used, and the condition is not limited.

In addition, deprotection in the step c) is preferably performed withoutusing a heavy metal catalyst as described above; however, it is possibleto perform the deprotection with a heavy metal catalyst. For example, inthe case in which the polyalkylene glycol derivative obtained by theproduction method of the present invention is used for applications inwhich mixing of a heavy metal does not cause a substantial problem (suchas, for example, cosmetics, hair growth agents, and surfactants), it isconsidered that the heavy metal catalyst may be used in the step c). Inthe case in which the step c) is performed with a heavy metal catalyst,the general heavy metal catalyst as described above may be usedaccording to a usual method, and the method is not particularly limited.

In the case in which deprotection is performed with an acid catalyst, aproduced amine represented by the general formula (III) and an acidforms a salt and the acid cannot be removed in some cases. In suchcases, when the produced basic compound is added to and is reacted withthe acid, a salt of the added basic compound and the acid is formed, andtherefore, the amine represented by the general formula (III) may beextracted. The produced salt may be removed by filtration. In the casein which the produced salt is incorporated into the polymer, the saltmay be removed with an adsorption material. As the adsorption material,the adsorption materials as described in the above-mentioned [Step b]may be used, although this is not particularly limited thereto. Theamount of adsorbent used may be 0.01 to 10 times, preferably 0.1 to 8times, more preferably 0.3 to 6 times the mass of the compoundrepresented by the general formula (III), although this is notparticularly limited. Examples of the basic compound for use includepotassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodiummethoxide, and potassium methoxide, although this is not limitedthereto. The amount of the basic compound added is, for example, 1 to 10equivalents, preferably 1 to 5 equivalents, more preferably 1 to 2equivalents, relative to the number of moles of the acid catalyst foruse in deprotection. As a solvent for use in filtration, the reactionsolvent may directly be used, or filtration may be performed aftersolvent substitution with a solvent in which a salt is easy toprecipitate. Specific examples of the solvent in which a salt is easy toprecipitate include ethers such as THF and 1,4-dioxane, aromatichydrocarbons such as benzene, toluene, and xylene, esters such as ethylacetate, n-butyl acetate, and γ-butyrolactone, ketones such as acetone,methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide(DMSO), N,N-dimethylformamide (DMF), and acetonitrile, although this isnot limited thereto. The aromatic hydrocarbons such as benzene, toluene,and xylene are preferred for the purpose of enhancing the filterability.These solvents may be used alone or in combination of two or more. Inthat case, the mixing ratio is not particularly limited.

In removing the acid catalyst, the adsorption material may directly beadded to the reaction system without adding a basic compound; however,in that case, there is a possibility that the filterability is lowered.Therefore, the adsorption material is preferably used after theabove-mentioned addition of the basic compound.

For example, crystallization of the compound represented by the generalformula (III) may be performed with a poor solvent directly afterdeprotection, crystallization may also be performed after solventsubstitution with a good solvent, or crystallization may also beperformed after the above-mentioned reaction with the basic compound andthe treatment with an adsorption material. In that case, specificexamples of the good solvent include ethers such as THF and 1,4-dioxane,aromatic hydrocarbons such as benzene, toluene, and xylene, esters suchas ethyl acetate, n-butyl acetate, and -γ-butyrolactone, ketones such asacetone, methyl ethyl ketone, and methyl isobutyl ketone, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), and acetonitrile,although this is not limited thereto. These solvents may be used aloneor in combination of two or more. In that case, the mixing ratio is notparticularly limited. The concentration of the compound after solventsubstitution is, for example, 5 to 50 mass %, preferably 10 to 40 mass%, more preferably 10 to 30 mass %.

The poor solvent for use in the crystallization of the compoundrepresented by the general formula (III) has a low solubility for thecompound represented by the general formula (III). Specific examples ofthe suitable poor solvent for use include hydrocarbon such as hexane,heptane, octane, nonan, decane, cyclopentane, cyclohexane, cycloheptane,and cyclooctane, and ethers such as diethyl ether, diisopropyl ether,and di-n-butyl ether. The amount of the poor solvent used is, forexample, 5 to 100 times, preferably 5 to 50 times, more preferably 5 to20 times the mass of a compound represented by the general formula(III), although this is not particularly limited thereto. The poorsolvents may be used alone or in combination of two or more.Alternatively, the poor solvent may be mixed with a different solventfor use. Examples of the different solvent for mixing include esterssuch as ethyl acetate, n-butyl acetate, and γ-butyrolactone, ketonessuch as acetone, methyl ethyl ketone, and methyl isobutyl ketone,hydrocarbons such as benzene, toluene, xylene, and cumene, ethers suchas tetrahydrofuran, diethyl ether, and 1,4-dioxane, alcohols such asmethanol, ethanol, isopropyl alcohol, and ethylene glycol monomethylether, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), andacetonitrile, although this is not limited thereto. In the case of usinga mixture of two or more solvents as a poor solvent, the mixing ratio isnot particularly limited.

In the [Step c], after precipitation of solid of the compoundrepresented by the general formula (III) by crystallization, the solidmay be washed for purification as needed. The solvent for use in washingis desirably the same poor solvent as described above, although this isnot particularly limited. The amount of the washing solvent used is alsonot particularly limited. The produced solid is dried under reducedpressure, so that the compound represented by the general formula (III)can be extracted as a solid.

In the present embodiment, since the amino group of the compoundrepresented by the general formula (III) is obtained by the deprotectionin the [Step c] as described above, by-products (compounds representedby the following (IV) to (VI)), that can be produced by, for example, amethod described in Japanese Patent No. 3562000, are not substantiallyproduced, and a narrowly distributed and high-purity polyalkylene glycolderivative having an amino group at an end, the polyalkylene glycolderivative represented by the general formula (III), can finally besynthesized. In contrast, in the case in which a cyanoethylated compoundis subjected to hydrogen reduction to lead to a polyalkylene glycolderivative having an amino group by, for example, a method described inJapanese Patent No. 3562000, the hydrogen reduction is accompanied byβ-elimination of acrylonitrile, and therefore, production of a PEGderivative represented by the following general formula (VI) cannot beprevented. Moreover, in the conventional method, there is a possibilitythat a secondary and tertiary amine compounds represented by thefollowing general formula (IV) and (V) are produced in the hydrogenreduction process due to addition of an amine as a product to an imineas a reduction intermediate of nitrile. The side reactions may besuppressed by adding ammonia or acetic acid to the reaction system;however, it is difficult to completely control the side reactions by aconventional method.HN

R_(A) ²—R_(A) ³—(OR_(A) ⁵)_(n)—OR_(A) ⁵)₂  (IV)N

R_(A) ²—R_(A) ³—(OR_(A) ⁵)_(n)—(OR_(A) ⁴)₃  (V)H—(OR_(A) ⁵)_(n)—OR_(A) ⁴  (VI)(In the general formulas (IV) to (VI), R_(A) ², R_(A) ³, R_(A) ⁴, R_(A)⁵, and n are the same as R_(A) ², R_(A) ³, R_(A) ⁴, R_(A) ⁵, and n inthe general formula (III).)[Post-Treatment Step]

After the step c), a post-treatment step of purifying the compoundrepresented by the general formula (III) with a strong acid cationexchange resin may optionally be performed. Moreover, in the case inwhich the protective group in the compound represented by the generalformula (II) obtained in the step b) is a protective group that isdeprotectable with an acid, this post-treatment step with a strong acidcation exchange resin may be performed after the step b) directly, sothat deprotection may be performed in parallel and the process may besimplified. That is to say, in this case, the step c) (step ofdeprotecting the compound represented by the general formula (II) toobtain the compound represented by the general formula (III)) mayspecifically be performed by the following operations of thepost-treatment step.

In the post-treatment step, the reaction product (crude product)containing the compound represented by the general formula (III)obtained in the step c) or the reaction product (crude product)containing the compound represented by the general formula (II) obtainedin the step b) is reacted with the strong acid cation exchange resin.Examples of the method for reacting the crude products obtained in thestep c) or the step b) with a strong acid cation exchange resin include:flowing the solution of the crude products in a column filled with theion exchange resin to-cause adsorption; and circulating the solution ofthe crude products between a cartridge filled with the resin and thereaction tank for the step c) or the step b); although this is notparticularly limited. Moreover, in the case in which the post-treatmentstep is performed after the step b), the compound represented by thegeneral formula (II) is reacted with water or a monohydric alcoholsolvent having 1 to 5 carbon atoms in the presence of the catalyst ofthe strong acid cation exchange resin, so that the compound representedby the general formula (III) may be adsorbed by the strong acid cationexchange resin after deprotection.

Specific examples of the strong acid cation exchange resin includingAMBERLITE series (IR120B, IR124B, 200CT, and 252) made by OrganoCorporation, AMBERJET series (1020, 1024, 1060, and 1220) made by OrganoCorporation, DIAION series (e.g. SK104, SK1B, SK110, SK112, PK208,PK212, PK216, PK218, PK220, PK228, UBK08, UBK10, UBK12, UBK510L, UBK530,and UBK550) made by Mitsubishi Chemical Corporation, DOWEX series (50W×250-100, 50W×2 100-200, 50W×4 100-200, 50W×8 50-100, 50W×8 100-200, 50W×8200-400, HCR-S, and HCR-W2(H)) made by Dow Chemical Co., are suitablyused although this is not limited thereto. The amount of the strong acidcation exchange resin used is, for example, 1 to 50 times, preferably 1to 30 times, more preferably 1 to 20 times the mass of the compoundrepresented by the general formula (III).

In the case of using a strong acid cation exchange resin, the strongacid cation exchange resin may be treated with an acid compound prior touse, since commercially available strong acid cation exchange resins areoften in an alkali metal sulfonate salt state, the pretreatment with anacid compound regenerates sulfo groups, so that the reaction efficiencycan be improved. In this case, examples of the acid compound for useinclude inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid, and perchloric acid, although this is not limitedthereto. The amount of the acid compound used is, for example, 1 to 15times, preferably 1 to 10 times, more preferably 1 to 8 times the massof the strong acid cation exchange resin. After treatment of the strongacid cation exchange resin with an acid compound, the acid compound maybe separated from the resin by washing with water, and water may beseparated by a water-soluble organic solvent such as methanol andethanol as needed.

In this post-treatment step, impurities other than the compoundrepresented by the general formula (III) (compound represented by thegeneral formula (VIII) and salts) may also be separated. That is to say,the crude products after the step c) or the step b) are reacted with astrong acid cation exchange resin to adsorb the compound represented bythe general formula (III) by the strong acid cation exchange resin, andthen the strong acid cation exchange resin is washed with water or themonohydric alcohol having 1 to 5 carbon atoms, so that substances otherthan the target compound represented by the general formula (III) can beseparated. Examples of the monohydric alcohol having 1 to 5 carbon atomsfor use in the washing include methanol, ethanol, n-propyl alcohol,isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butylalcohol, n-pentyl alcohol, isopentyl alcohol, and neopentyl alcohol,although this is not limited thereto. In performing washing, water or amonohydric alcohol may be used alone, or a mixture of water and one ormore alcohols or a mixture of two or more alcohols may be used. In thatcase, the mixing ratio is not particularly limited. The amount of wateror a monohydric alcohol having 1 to 5 carbon atoms used is, for example,1 to 30 times, preferably 1 to 20 times, more preferably 1 to 10 timesthe mass of the strong acid cation exchange resin for use, although thisis not particularly limited.

The strong acid cation exchange resin with the adsorbed compoundrepresented by the general formula (III) is reacted with a basiccompound in water or a monohydric alcohol having 1 to 5 carbon atoms, sothat a compound represented by the general formula (III) may beextracted in water or the monohydric alcohol. In performing thereaction, water or the monohydric alcohol may be used alone, or amixture of water and one or more alcohols or a mixture of two or morealcohols may be used. In that case, the mixing ratio is not particularlylimited. Examples of the method for reacting a strong acid cationexchange resin and a basic compound include: flowing the solution ofbasic compound in a column filled to cause reaction; and circulating thesolution of the basic compound between a cartridge filled with the resinand the reaction tank for the [Step c]; although this is notparticularly limited.

Examples of the monohydric alcohol for use in the extraction includemethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol,sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, isopentylalcohol, and neopentyl alcohol. The amount of water or a monohydricalcohol used is, for example, 1 to 30 times, preferably 1 to 20 times,more preferably 1 to 10 times the mass of the strong acid cationexchange resin for use, although this is not particularly limited.

As the basic compound for use in the extraction, ammonia dissolved inwater or an organic solvent (e.g. ammonia water and methanol solution ofammonia) may be suitably used, and primary, secondary and tertiaryaliphatic amines, mixed amines, aromatic amines, and heterocyclic aminesmay be also used. Examples of the primary aliphatic amines includemethylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine,isobutylamine, sec-butylamine, tert-butylamine, and ethylene diamine;examples of the secondary aliphatic amines include dimethylamine,diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine,diisobutylamine, di-sec-butylamine; examples of the tertiary aliphaticamines include trimethylamine, triethylamine, tri-n-propylamine,triisopropylamine, tri-n-butylamine, tri-isobutylamine, andtri-sec-butylamine; examples of the mixed amines includedimethylethylamine, methylethylpropylamine, benzylamine, phenethylamine,benzyldimethylamine; specific examples of the aromatic amines and theheterocyclic amines include aniline derivatives (e.g. aniline,N-methylaniline, N-ethylaniline, N-propylaniline, N,N-dimethylaniline,2-methylaniline, 3-methylaniline, 4-methylaniline, ethylaniline,propylaniline, trimethylaniline, 2-nitroaniline, 3-nitroaniline,4-nitroaniline, 2,4-dinitroaniline, 2,6-dinitroaniline,3,5-dinitroaniline, and N,N-dimethyltoluidine), diphenyl(p-tolyl)amine,methyldiphenylamine, triphenylamine, phenylenediamine, naphthylamine,diaminonaphthalene, and pyridine derivatives (e.g. pyridine,methylpyridine, ethylpyridine, propylpyridine, butylpyridine,4-(1-butylpentyl)pyridine, dimethylpyridine, trimethylpyridine,triethylpyridine, phenylpyridine, 3-methyl-2-phenylpyridine,4-tert-butylpyridine, diphenylpyridine, benzylpyridine, methoxypyridine,butoxypyridine, dimethoxypyridine, 4-pyrrolidinopyridine,2-(1-ethylpropyl)pyridine, aminopyridine, and dimethylaminopyridine),although this is not limited thereto. Alternatively an alkali aqueoussolution such as potassium hydroxide and sodium hydroxide may be used asa basic compound. The amount of the basic compound used is, for example,0.1 to 100 times, preferably 0.1 to 10 times, more preferably 0.1 to 5times the mass of the strong acid cation exchange resin for use.

In this way, the steps a) to c) are performed, or the pre-steps 1 and 2and/or the post-treatment step are further performed optionally beforeand/or after the steps a) to c), so that the compound represented by thegeneral formula (III) (narrowly distributed and high-purity polyalkyleneglycol derivative having an amino group at an end) can be produced.

That is to say, according to another aspect, the present inventionrelates to a narrowly distributed and high-purity polyalkylene glycolderivative having an amino group at an end, the polyalkylene glycolderivative obtained in the above-described production method andrepresented by the general formula (III).

Regarding the compound: obtained after performing the steps a) to c), orobtained by further performing the pre-steps 1 and 2 and/or thepost-treatment step optionally before and/or after the steps a) to c);and represented by the general formula (III), the initiation reaction issufficiently faster than the propagation reaction during polymerization,the amount of water mixed as a factor of termination reaction is small,and further the polymerization initiator is uniformly dissolved in thepolymerization solvent, so that a narrowly distributed polymer can beobtained. That is to say, the compound produced by the production methodof the present embodiment and represented by the general formula (III)is narrowly distributed, and the dispersity (weight average molecularweight (Mw)/number average molecular weight (Mn)) is, for example, 1.0to 1.20, preferably 1.0 to 1.10, more preferably 1.0 to 1.06. Moreover,the molecular weight of the compound represented by the general formula(III) produced by the production method of the present invention ispreferably 5,000 to 25,000, more preferably 8,000 to 15,000 as theweight average molecular weight (Mw). The molecular weight anddispersity of a polymer in the present embodiment are defined as valuesobtained in the case in which measurement is performed with gelpermeation chromatography (hereinafter, alleviated as “GPC”).

Regarding the amount of compounds represented by the general formulas(IV) and (V) mixed in the product obtained after performing the steps a)to c), or obtained by further performing the pre-steps 1 and 2 and/orthe post-treatment step optionally before and/or after the steps, a) toc) expressed by an area content ratio (%), the area of the compoundsrepresented by the general formulas (IV) and (V) is preferably 3% orless, more preferably 2% or less, relative to the total area of thecompounds represented by the general formulas (III), (IV), and (V). Mostpreferably, the obtained product does not contain any one of thecompounds represented by the general formula (IV) and represented by thegeneral formula (V). According to the present embodiment, any one of thecompound represented by the general formula (IV) and the compoundrepresented by the general formula (V) are not actually produced. Thesecondary amine represented by the general formula (IV) and the tertiaryamine represented by the general formula (V) have a molecular weighttwice or three times as large as the molecular weight of thepolyalkylene glycol derivative represented by the general formula (III)as a main product, and, therefore, the amount of these amines producedcan be confirmed by GPC.

The amount of the compound represented by the general formula (VI) mixedin the product obtained after performing the steps a) to c), or obtainedby further performing the pre-steps 1 and 2 and/or the post-treatmentstep optionally before and/or after the steps a) to c) is preferably 2mol % or less, more preferably 1 mol % or less, relative to the totalamount of substances of the compound represented by the general formula(III) and the compound represented by the general formula (VI). Mostpreferably, the obtained product does not contain a compound representedby the general formula (VI). According to the present embodiment, acompound represented by the general formula (VI) is not actuallyproduced. The compound represented by the general formula (VI) containsan alcohol as a functional group, and therefore the content ratio interms of composition ratio (mol %) can be determined by comparing with amethylene of amine of the polyalkylene glycol derivative represented bythe general formula (III) as a main product from proton magneticresonance (1H-NMR).

Moreover, the product obtained after performing the steps a) to c), orobtained by further performing the pre-steps 1 and 2 and/or thepost-treatment step optionally before and/or after the steps a) to c)does not substantially contain such by-products (compounds representedby the general formulas (IV) to (VI)) that can be produced in theconventional methods as described above. Specifically,X_(A)/(X_(A)+X_(B)) is preferably 0.95 or more, more preferably 0.97 ormore, where X_(A) represents the total amount of the compoundrepresented by the general formula (III) as the main product, X_(B)represents the total amount of by-products containing the compoundsrepresented by the general formula (IV), the general formula (V), andthe general formula (VI) respectively, and both X_(A) and X_(B) areconverted from the measurement results by GPC and 1H-NMR as describedabove. Most preferably, the obtained product does not contain suchby-products as described above. According to the present embodiment,these by-products are not actually produced.

Moreover, the content of heavy metal impurities measured by a highfrequency inductively coupled plasma mass spectrometer (ICP-MS) in theproduct obtained after performing the steps a) to c), or obtained byfurther performing the pre-steps 1 and 2 and/or the post-treatment stepoptionally before and/or after the steps a) to c) is preferably 100 ppbor less, more preferably 10 ppb or less. The measurement of the amountof heavy metal impurities in the product described above is generallyperformed with the above-described ICP-MS; however, the measurementmethod is not limited thereto. A polymer sample, when analyzed with anICP-MS, may be diluted with a solvent for measurement. It is essentialthat a solvent used dissolve the polymer and not contain a metal.Ultrapure water and N-methyl-2-pyrrolidone for electronic industry areparticularly preferred; however, the solvent is not limited thereto. Thedilution ratio is preferably 10 to 100,000 times, more preferably 50 to1,000 times, although this is not limited thereto.

As described above, in the conventional synthesis methods described in,for example, Japanese Patent No. 3050228 and Japanese Patent No.3562000, a cyano group is converted to an aminomethyl group with a Raneynickel catalyst, and therefore, for example, in the case in which thepolyalkylene glycol derivative is used in medical supplies, there isconcern over mixing of a heavy metal in the product. According to “ICHQ3D: GUIDELINES FOR ELEMENTAL IMPURITIES Draft ICH consensus Guideline”reported in International Conference on Harmonization of TechnicalRequirements for Registration of Pharmaceuticals for Human Use, aselementary impurities that need risk assessment among elementaryimpurities, As, Pb, Cd, and Hg are listed in Class 1, V, Mo, Se, and Coare listed in Class 2A, Ag, Au, Tl, Pd, Pt, Ir, Os, Rh, and Ru arelisted in Class 2B, and Sb, Ba, Li, Cr, Cu, Sn, and Ni are listed inClass 3. Examples of the heavy metal for use in hydrogen reductioninclude Co, Ni, Pd, Pt, Rh, Ru, Cu, and Cr; however, these metals arelisted as the metals that need risk assessment, and reducing the mixingamount thereof will be required more and more in the future. In thisregard, since the method of the present embodiment does not require theuse of a heavy metal catalyst as described above, a heavy metal is notmixed in a product. As a result thereof, the method of the presentinvention is a production method that is particularly suitable forobtaining a compound represented by the general formula (III) for use inmedical supplies.

Embodiment 2

In the present invention, the compound represented by the followinggeneral formula (1) and/or the following general formula (2) the aminogroup of which is silyl-protected (hereinafter, sometimes noted as“compounds represented by the general formulas (1) and/or (2)” as anabbreviation, and the same applies to the other compounds) arepreferably used as a polymerization initiator, among the above-describedembodiment 1. The compounds represented by the general formulas (1)and/or (2) have advantages of having a high solubility to polymerizationsolvents, moreover having a high stability as a polymerizationinitiator, and furthermore being easily deprotectable with an acid afterpolymerization. Hereinafter, the embodiment in which the compoundsrepresented by the general formulas (1) and/or (2) are used as apolymerization initiator is sometimes referred to as “embodiment 2”. Inaddition, the present embodiment 2 is a preferred embodiment of theembodiment 1, and therefore, the description is omitted in theoverlapping portions.

The compound represented by the following general formula (1) representsa compound represented by the general formula (I) in the embodiment 1where R_(A) ^(1a) and R_(A) ^(1b) each have a structure represented bySi(R¹)₃, R_(A) ² represents R², and R_(A) ³ represents (OR⁵)_(m).

Moreover, the compound represented by the following general formula (2)represents a compound represented the general formula (I) in theembodiment 1 where R_(A) ^(1a) and R_(A) ^(1b) each have a structurerepresented by Si(R¹)₃, R_(A) ² represents R³, and R_(A) ³ represents asingle bond.

A method for producing a polyalkylene glycol derivative in the case inwhich the compounds represented by the general formulas (1) and/or (2)are used as a polymerization initiator in the present embodiment 2 isdescribed as steps a′) to c′) as follows. As shown in the following, inthe case in which the compound represented by the general formula (1) isused as a polymerization initiator, the polyalkylene glycol derivativeto be obtained is the compound represented by the general formula (3),and in the case in which the compound represented by the general formula(2) is used as a polymerization initiator, the polyalkylene glycolderivative to be obtained is the compound represented by the generalformula (4).

Step a′) a step of reacting the polymerization initiator represented bythe general formulas (1) and/or (2) with an alkylene oxide in apolymerization solvent to obtain compounds represented by the followinggeneral formulas (12) and/or (13),

Step b′) a step of reacting the compounds represented by the generalformulas (12) and/or (13) with a compound represented by the followinggeneral formula (5) to obtain compounds represented by the followinggeneral formulas (14) and/or (15), and

Step c′) a step of deprotecting the compounds represented by the generalformulas (14) and/or (15) to obtain compounds represented by the generalformulas (3) and/or (4).

In the general formulas (1) to (2), and (12) to (15), R¹ eachindependently represent a linear monovalent hydrocarbon group having 1to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon grouphaving 3 to 6 carbon atoms. Alternatively, R¹ may bind to each other toform a 3 to 6 membered ring together with a silicon atom having bondswith R¹. Specific examples of R¹ include a methyl group, an ethyl group,an n-propyl group, an isopropyl group, an n-butyl group, an isobutylgroup, a tert-butyl group, an n-pentyl group, an n-hexyl group, acyclopropyl group, a cyclobutyl group, a cyclopentyl group, and acyclohexyl group. Moreover, in the case in which R¹ bind to each otherto form a ring together with a silicon atom, examples of R¹ include agroup obtained by eliminating one hydrogen atom from the above-listedgroups (in addition, as described above, R¹ in the present embodiment 2is a discrete sign the definition of which is different from thedefinition of R_(A) ^(1a) and/or R_(A) ^(1b) in the embodiment 1, and isthe same as R¹ in “(P-1) a protective group of a structure representedby Si(R¹)₃” described in the embodiment 1). R¹ is preferably the methylgroup, the ethyl group, the n-propyl group, and the isopropyl group fromthe viewpoint of easiness of introducing two protective groups onnitrogen to easily synthesize the compounds represented by the generalformulas (6) and/or (7) as will be described later.

In the general formulas (1), (3), (12), and (14), R² represents a lineardivalent hydrocarbon group having 1 to 6 carbon atoms, or a branched orcyclic divalent hydrocarbon group having 3 to 6 carbon atoms. Specificexamples of R² include a group obtained by eliminating one hydrogen atomfrom each of a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, an isobutyl group, a tert-butylgroup, an n-pentyl group, an n-hexyl group, a cyclopropyl group, acyclobutyl group, a cyclopentyl group, and a cyclohexyl group. R² in thepresent embodiment 2 corresponds to R_(A) ² in the embodiment 1, and thedefinition of R² is the same as the definition of R_(A) ² in theembodiment 1.

In the general formulas (2), (4), (13), and (15), R³ represents a lineardivalent hydrocarbon group having 4 to 6 carbon atoms. Specific examplesof R³ include a group obtained by eliminating one hydrogen atom fromeach of an n-butyl group, an n-pentyl group, and an n-hexyl group. R³ inthe present embodiment 2 is a discrete sign the definition of which isdifferent from the definition of R_(A) ³ in the embodiment 1 asdescribed above.

In the general formulas (3) to (5) and (14) to (15), R⁴ represents ahydrogen atom, or a linear, branched, or cyclic hydrocarbon group thatmay be substituted, the hydrocarbon group having 1 to 12 carbon atoms,and the hydrocarbon group may contain a heteroatom. Specific examples ofR⁴ include a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, an isobutyl group, a tert-butylgroup, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexylgroup, an octyl group, a decyl group, a dodecyl group, a phenyl group,an o-tolyl group, an m-tolyl group, a p-tolyl group, a 2,3-xylyl group,a 2,4-xylyl group, a 2,5-xylyl group, a 2,6-xylyl group, a 3,4-xylylgroup, a 3,5-xylyl group, a mesityl group, a vinyl group, and an allylgroup. Examples of R⁴ of a substituted structure include an acetalatedformyl group, a cyano group, a formyl group, a carboxyl group, an aminogroup, an alkoxycarbonyl group having 1 to 6 carbon atoms, an acylamidegroup having 2 to 7 carbon atoms, tri(same or different alkyl having 1to 6 carbon atoms)siloxy group, a siloxy group, a silylamino group, amaleimide group, a thiol group, a hydroxide group, a methacryloyloxygroup, an acryloyloxy group, an active ester group, and an azi group.Specific examples of R_(A) ⁴ having a substituent include substituentsrepresented by the following structures, although this is not limitedthereto. The following formulas each represent an end portion of R⁴ of asubstituted structure, and the dotted lines in the formulas show that ahydrocarbon portion of R⁴ can have variations as described above. Suchsubstituents may further be protected by freely selected appropriateprotective groups.

R⁴ in the present embodiment 2 corresponds to R_(A) ⁴ in the embodiment1, and the definition of R⁴ is the same as the definition of R_(A) ⁴ inthe embodiment 1.

In the general formulas (1), (3) to (5), and (12) to (15), R⁵ representsan alkylene group having 2 to 8 carbon atoms. Among others, R⁵ ispreferably an alkylene group having 2 to 3 carbon atoms. That is to say,R⁵ is preferably an ethylene group or a propylene group. In addition,the (OR⁵) unit may be constituted from a single kind of oxyalkylenegroup, for example, from only an oxyethylene or oxypropylene group, ortwo or more kinds of oxyalkylene groups may be mixed together. In thecase in which two or more kinds of oxyalkylene groups are mixedtogether, (OR⁵) may be constituted from two or more kinds of differentoxyalkylene groups by random polymerization or block polymerization. Inaddition, R⁵ in the present embodiment 2 corresponds to R_(A) ⁵ in theembodiment 1, and the definition of R⁵ is the same as the definition ofR_(A) ⁵ in the embodiment 1.

In the general formulas (1) to (2), and (12) to (13), M represents analkali metal, and specific examples of M are as described in theembodiment 1.

In the general formulas (1), (3), (12), and (14), m represents aninteger of 1 to 3. Considering the boiling point of a compound whendistilled, m is preferably an integer of 1 to 2.

Moreover, in the general formulas (1) to (4), and (12) to (15), r, k, n,and L are the same as r, k, n, and L described in the embodiment 1.

In selecting each of the compounds for use in each step in theproduction method of the present embodiment 2, desired R¹, R², R³, R⁴,R⁵, m, r, k, n, and L in the general formulas (1), (2), (5), and (12) to(15) may be selected so that the compounds represented by the generalformulas (3) and/or (4) as the desired final products may be obtained.

Moreover, in the present embodiment 2, [Pre-step 1′] and [Pre-step 2′]may be performed as an optional step prior to the steps a′) to c′). The[Pre-step 1′] and [Pre-step 2′] include: a step ([Pre-step 1′]) ofproducing compounds represented by the following general formulas (6)and/or (7) as a raw material (starting material) of the polymerizationinitiator; and a step ([Pre-step 2′]) of producing compounds representedby the general formulas (1) and/or (2) as a polymerization initiator. Asthe pre-step, the [Pre-step 2′] may be performed subsequent to the[Pre-step 1′], or the [Pre-step 2′] may only be performed not throughthe [Pre-step 1′].

Moreover, in the present embodiment 2, a post-treatment step ofpurifying a produced target substance (compounds represented by thegeneral formulas (3) and/or (4)) may be performed as an optional stepafter the steps a′) to c′).

The preferred embodiment 2 will be described below in the order of the[Pre-step 1′], the [Pre-step 2′], the steps a′) to c′), and thepost-treatment step along time series. The description willappropriately be omitted for passages the content of which is the sameas those in the embodiment 1.

[Pre-Step 1′]

The [Pre-step 1′] is a step of synthesizing the compound represented bythe following general formulas (6) and/or (7) used as a precursor of thepolymerization initiator.

(In the general formulas (6) and (7), R¹, R², R³, R⁵, and m are the sameas defined in the general formulas (1) and (2))

The [Pre-step 1′] may be performed in, for example, the following steps(1-1) to (1-2) and/or the following steps (2-1) to (2-2), although thisis not limited thereto.

(In the general formulas (6a), (6b), (7a), (8), and (9), R′, R², R³, R⁵,and m are the same as defined in the general formulas (1) and (2), L¹represents a leaving group, specific examples thereof are as describedin the embodiment 1, and R⁶ represents a hydrocarbon group having 1 to 5carbon atoms.)

Specific examples of R⁶ include a methyl group, an ethyl group, ann-propyl group, an isopropyl group, an n-butyl group, an isobutyl group,a tert-butyl group, an n-pentyl group, a cyclopropyl group, a cyclobutylgroup, and a cyclopentyl group, although this is not limited thereto.

A silicon-nitrogen bond is generally weaker than a silicon-oxygen bond,and therefore, in the deprotection reaction as represented by theformulas (1-2) and (2-2), the silicon-nitrogen bond is fundamentallycleaved in a preferential manner. However, in the case of the presentreaction in the present embodiment 2, two bulky protective groups(trialkylsilyl groups) are present on the nitrogen atom, thesilicon-oxygen bond can be cleaved in a preferential manner due tosteric hindrance of the protective groups. In this way, after the aminogroup is protected by two bulky protective groups and the hydroxy groupis also protected by a protective group of the same structure (that is,after all the three protective groups are introduced in the amino groupand the hydroxy group), only the hydroxy group is deprotected in apreferential manner making use of bulk due to the presence of twoprotective groups on the amino group, so that an alcohol in which onlythe amino group is silylated can be synthesized. Such alcohol has beendifficult to synthesize by conventional methods.

The steps (1-1) and/or (2-1) may be performed, for example, in thefollowing manner. Reaction may be performed by adding a basic compoundto the compounds represented by the general formulas (6a) and/or (7a)without a solvent, and subsequently dripping the compound represented bythe general formula (6b) to mix, or, reaction may be performed bydissolving the compounds represented by the general formulas (6a) and/or(7a) in a proper solvent, then adding a basic compound, and thendripping the compound represented by the general formula (6b) to mix.The amount of the compound represented by the general formula (6b) usedis, for example, 3 to 15 times, preferably 3 to 10 times, morepreferably 3 to 5 times the number of moles of the compounds representedby the general formulas (6a) and/or (7a).

In the case in which a solvent is used in the steps (1-1) and/or (2-1),specific examples of the solvent include ethers such as THF and1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene,halogens such as methylene chloride, and N,N-dimethylformamide,N-methyl-2-pyrrolidone, acetonitrile, and acetone, although this is notlimited thereto. The amount of the solvent used is, for example, 1 to 20times, preferably 2 to 10 times, more preferably 2 to 5 times the massof the compounds represented by the general formulas (6a) and/or (7a),although this is not particularly limited thereto.

As specific examples of the basic compound for use in the steps (1-1)and/or (2-1), hydroxides such as sodium hydroxide, potassium hydroxide,and tetramethylammonium hydroxide, carbonates such as sodium carbonate,potassium carbonate, and cesium carbonate, metal alkoxides such assodium methoxide, sodium ethoxide, and potassium t-butoxide, metalhydrides such as sodium hydride, and potassium hydride, and primary,secondary, and tertiary aliphatic amines, conjugated amines, aromaticamines, heterocyclic amines, and ammonia water may be used although thisis not limited thereto. The amount of the basic compound used is, forexample, 3 to 15 times, preferably 3 to 10 times, more preferably 3 to 5times the mass of the compounds represented by the general formulas (6a)and/or (7a).

The reaction temperature in the steps (1-1) and/or (2-1) may be within arange from the melting point to the boiling point of the solvent used,and is, for example, −60° C. to 150° C., preferably 0° C. to 80° C. Thecompletion of the reaction in the steps (1-1) and/or (2-1) can beassumed when the compounds represented by the general formulas (6a)and/or (7a) analyzed by gas chromatography disappear or when thecompounds represented by the general formulas (8) and/or (9) areobtained as main products.

Moreover, the steps (1-2) and/or (2-2) may be performed by, for example,treating, with a base, the compounds represented by the general formulas(8) and/or (9). Specifically, the steps (1-2) and/or (2-2) may beperformed, for example, in the following manner After the compoundsrepresented by the general formulas (8) and/or (9) are once purified andextracted, selective deprotection is performed by dissolving thecompounds represented by the general formulas (8) and/or (9) in R⁶OH andadding a catalytic amount of R⁶ONa. Produced (R¹)₃SiOR⁶ is distilledaway under reduced pressure together with R⁶OH to bias the equilibriumfrom the general formulas (8) and/or (9) toward the general formulas (6)and/or (7). R⁶OH is added again to further perform the reaction, and theoperation of distilling produced (R¹)₃SiOR⁶ away is repeated to make itpossible to complete the reaction. The amount of R⁶OH used is, forexample, 1 to 20 times, preferably 2 to 15 times, more preferably 3 to10 times the mass of the compounds represented by the general formulas(8) and/or (9), although this is not particularly limited thereto. Theamount of R⁶ONa used is, for example, 0.01 to 1 times, preferably 0.01to 0.5 times, more preferably 0.01 to 0.1 times the number of moles ofthe compounds represented by the general formulas (8) and/or (9),although this is not particularly limited thereto.

The reaction temperature in the steps (1-2) and/or (2-2) is, forexample, 0° C. to 100° C., preferably 30° C. to 80° C. The completion ofthe reaction in the steps (1-2) and/or (2-2) can be assumed when thecompounds represented by the general formulas (8) and/or (9) analyzed bygas chromatography disappear. The compounds represented by the generalformulas (6) and/or (7) are preferably purified by distillation toremove water. In that case, the water content ratio of the compoundsrepresented by the general formulas (6) and/or (7) is, for example, 50ppm or less, preferably 10 ppm or less, more preferably 5 ppm or less.

Examples of the other methods for producing the compounds represented bythe general formulas (6) and/or (7) include such methods as thefollowing steps (1-3) to (1-4), the following steps (1-5) to (1-6), andthe following steps (2-3) to (2-4), although this is not limitedthereto.

(In the general formulas (6b), (6c), (6d), (6e), (6f), (7b), and (7c),R′, R², R³, R⁵, and m are the same as defined in the general formulas(1) and (2), L¹ and L² each represent a leaving group, the specificexamples thereof are as described in the embodiment 1, TsCl isabbreviation of p-toluenesulfonyl, and MSCl is abbreviation ofmethanesulfonyl chloride.)

The steps (1-3) and (2-3) may be performed by the same method as in thestep (i-2) described in the embodiment 1.

The steps (1-4) and (1-6) may be performed by the same method as in thestep (i-3) described in the embodiment 1. In the case of the reactionrepresented by (1-4) or (1-6), as described in the step (i-3) in theembodiment 1, use of an excessive amount of a diol makes it possible toetherify an alcohol at one end.

The step (1-5) may be performed, for example, in the following mannerReaction may be performed, using, as a starting material, the compoundrepresented by the general formula (6e) synthesized by the same methodas in the step (i-1) described in the embodiment 1, by adding a basiccompound to the compound represented by the general formula (6e) withouta solvent, and then adding TsCl or MSCl to mix, or, reaction may beperformed by dissolving the compound represented by the general formulas(6e) in a proper solvent, then adding a basic compound, and then addingTsCl or MsCl to the solution to mix. The amount of TsCl or MsCl used is,for example, 1 to 5 times, preferably 1 to 3 times, more preferably 1 to2 times the number of moles of the compound represented by the generalformula (6e).

In the case in which a solvent is used in the step (1-5), specificexamples of the solvent include ethers such as THF and 1,4-dioxane,aromatic hydrocarbons such as benzene, toluene, and xylene, halogenssuch as methylene chloride, and N,N-dimethylformamide,N-methyl-2-pyrrolidone, and acetonitrile, although this is not limitedthereto. The amount of the solvent used is, for example, 1 to 20 times,preferably 2 to 10 times, more preferably 2 to 5 times the mass of thecompound represented by the general formula (6e), although this is notparticularly limited thereto.

As specific examples of the basic compound for use in the step (1-5)include hydroxides such as sodium hydroxide, potassium hydroxide, andtetramethylammonium hydroxide, carbonates such as sodium carbonate,potassium carbonate, and cesium carbonate, metal alkoxides such assodium methoxide, sodium ethoxide, and potassium t-butoxide, metalhydrides such as sodium hydride and potassium hydride, and primary,secondary, and tertiary aliphatic amines, conjugated amines, aromaticamines, heterocyclic amines, and ammonia water may be used, althoughthis is not limited thereto. The amount of the basic compound used is,for example, 3 to 15 times, preferably 3 to 10 times, more preferably 3to 5 times the mass of the compound represented by the general formula(6e).

The reaction temperature in the step (1-5) may be within a range fromthe melting point to the boiling point of the solvent used, and is, forexample, −60° C. to 150° C., preferably 0° C. to 80° C. The completionof the reaction in the step (1-5) can be assumed when the compoundrepresented by the general formula (6e) analyzed by gas chromatographydisappears.

The step (2-4) may be performed, for example, in the following manner.

Reaction may be performed, using, as a starting material, the compoundrepresented by the general formula (7c) synthesized in the step (2-3),by adding a sodium hydroxide aqueous solution without a solvent to mix,or, reaction may be performed by dissolving the compound represented bythe general formula (7c) in a proper solvent, and then adding a sodiumhydroxide aqueous solution to mix. The amount of sodium hydroxide usedis, for example, 1 to 5 times, preferably 1 to 3 times, more preferably1 to 2 times the number of moles of the compound represented by thegeneral formula (7c).

In the case in which a solvent is used in the step (2-4), specificexamples of the solvent include H₂O, ethers such as THF and 1,4-dioxane,aromatic hydrocarbons such as benzene, toluene, and xylene, halogenssuch as methylene chloride, and N,N-dimethylformamide,N-methyl-2-pyrrolidone, and acetonitrile, although this is not limitedthereto. The amount of the solvent used is, for example, 1 to 20 times,preferably 2 to 10 times, more preferably 2 to 5 times the mass of thecompound represented by the general formula (7c), although this is notparticularly limited thereto.

The reaction temperature in the step (2-4) may be within a range fromthe melting point to the boiling point of the solvent used, and is, forexample, −60° C. to 100° C., preferably −30° C. to 20° C. The completionof the reaction in the step (2-4) can be assumed when the compoundrepresented by the general formula (7c) analyzed by gas chromatographydisappears.

[Pre-Step 2′]

The [Pre-step 2′] is a step of reacting the compounds represented by thegeneral formulas (6) and/or (7) with an alkali metal or an alkali metalcompound to obtain the compounds represented by the following generalformulas (1) and/or (2).

The reaction of the [Pre-step 2′] may be performed in the same manner asin the pre-step 2 in the embodiment 1. That is to say, the kind andamount of the alkali metal or alkali metal compound used, the kind andamount of the solvent used, the method for adding the compounds to thereaction system, and the reaction temperature may be appropriatelyselected within the range as described in the pre-step 2 in theembodiment 1. Moreover, as the solvent for use in the [Pre-step 2′], asolvent of the same kind as the polymerization solvent for use inpolymerization is used, so that whether the polymerization initiatordissolves or not in the polymerization solvent can be confirmed inadvance during the synthesis of the polymerization initiator. Theconfirmation method is the same as described in the pre-step 2 in theembodiment 1.

As described above, in the polymerization reaction, the water content inthe reaction system containing the compounds represented by the generalformulas (1) and/or (2) (polymerization initiator) is required to bereduced as low as possible in order to suppress the production of a diolpolymer as a by-product. Regarding this, a compound represented by thegeneral formula (6) with, for example, R¹=an ethyl group, R²═CH₂CH₂CH₂,m=1, and a high boiling point of 120° C. (10 Pa) and a compoundrepresented by the general formula (7) with R¹=an ethyl group,R³═CH₂CH₂CH₂CH₂CH₂CH₂ and a high boiling point of 110° C. (10 Pa) have asufficient difference in boiling point from water, so that separation ofwater can be achieved by drying under reduced pressure. Therefore, it ispreferred that, prior to the addition of the alkali metal or the alkalimetal compound in the [Pre-step 2′], the compounds represented by thegeneral formulas (6) and/or (7) be sufficiently dried under reducedpressure and then distilled. The range of the water content ratio of thecompounds represented by the general formulas (6) and/or (7) is the sameas the range of the water content ratio of the compound described in thepre-step 2 in the embodiment 1 and represented by the general formula(i).

As described above, in order to increase the polymerization rate, apolymerization initiator having a small amount of a residual alcohol asan initiator raw material is preferably used. Specifically, it ispreferred that the ratio of the amounts of substances between thepolymerization initiator represented by the general formulas (1) and/or(2) and the alcohol that is an initiator raw material represented by thegeneral formulas (6) and/or (7) after completion of the synthesis of thepolymerization initiator in the [Pre-step 2′] be in the same range asthe range of the ratio of the amounts of substances between thepolymerization initiator represented by the general formula (I) and thealcohol that is an initiator raw material represented by the generalformula (i) as described in the pre-step 2 in the embodiment 1.Moreover, it is possible to distill away the alcohol represented by thegeneral formulas (6) and/or (7) under reduced pressure after thepolymerization initiator is synthesized, and also in that case, it ispreferred that the ratio of the amounts of substances between thepolymerization initiator represented by the general formulas (1) and/or(2) and the alcohol represented by the general formulas (6) and/or (7)is in the same range as the range of the ratio of the amounts ofsubstances between the polymerization initiator represented by thegeneral formula (I) and the alcohol represented by the general formula(i) as described in the pre-step 2 in the embodiment 1.

[Step a′)]

The step a′) is a step of reacting the compounds represented by thegeneral formulas (1) and/or (2) with an alkylene oxide in apolymerization solvent. The compound represented by the general formulas(1) and/or (2) are desirably reacted with the alkylene oxide after thecompounds represented by the general formulas (1) and/or (2) arecompletely dissolved in the polymerization solvent. According to thestep a′), the compounds represented by the following general formulas(12) and/or (13) can be obtained. As the polymerization initiator, onlyone of the compounds represented by the general formula (1) and thecompounds represented by the general formula (2) may be used, or bothmay be used together.

Since the silicon-oxygen bond is generally stronger than thesilicon-nitrogen bond, there is a possibility that exchange reactionbetween the silicon-nitrogen bond and the silicon-oxygen bond progresseswithin a molecule during synthesis of a silyl-protected aminogroup-containing alkoxide in the case in which a five-membered ring orsix-membered ring structure containing a silicon-oxygen bond can beformed. Therefore, when polymerization is tried using, for example, acompound represented by the following general formula (0a) as apolymerization initiator, polymerization progresses from the amino groupside, not from the alkoxide side, and a target polyalkylene glycolderivative cannot be obtained. In contrast, in the polymerizationinitiator (for example, the following formulas (1a) and (2a))represented by the general formulas (1) and/or (2) for use in thepresent embodiment 2, production of the five-membered or six-memberedring containing a silicon-oxygen bond is suppressed by extending thelength of a chain that connects nitrogen and oxygen that constitutesO⁻M⁺ to 4 or more, so that a stable structure can be formed in a stateof being an alkoxide. As a result thereof, polymerization progressesfrom the alkoxide side, and the target polyalkylene glycol derivativecan be obtained.

The silyl-protected amino group-containing alcohol derivativesrepresented by the general formulas (1) and/or (2) which are used as apolymerization initiator each have a structure similar to that of thepolymerization solvent within each molecule, and therefore can dissolvein the polymerization solvent in the absence of an alcohol that is aninitiator raw material. The polymerization initiator represented by thegeneral formula (1) in particular has an alkylene oxide structure withinthe molecule to enhance the compatibility between the polymerizationinitiator and the polymerization solvent in the case in which thesolvent is, for example, an ether-based solvent such as THF, andtherefore, the polymerization initiator can dissolve in thepolymerization solvent in the absence of the alcohol. Moreover, thepolymerization initiator represented by the general formula (2) inparticular has a hydrocarbon structure represented by R³ within themolecule to enhance the compatibility between the polymerizationinitiator and the polymerization solvent in the case in which thesolvent is, for example, a hydrocarbon-based solvent such as toluene,and therefore, the polymerization initiator can dissolve in thepolymerization solvent in the absence of the alcohol. As a resultthereof, polymerization in a uniform system under mild conditionsbecomes possible, making it possible to produce a narrowly distributedpolyalkylene glycol derivative.

The reaction in the step a′) may be performed in the same manner asdescribed in the step a) in the embodiment 1. That is to say, the kindand amount of the polymerization solvent used, the method for adding thealkylene oxide to the reaction system, and the reaction temperature mayappropriately be selected within the range as described in the step a)in the above-described embodiment.

Among others, in the case in which the polymerization initiatorrepresented by the general formula (1) is used, the polymerizationinitiator has an alkylene oxide structure within the molecule, andtherefore, a cyclic ether compound having 4 to 10 carbon atoms, or alinear or branched ether compound, is preferably used as apolymerization solvent. Specific examples of the cyclic ether compound,and the linear or branched ether compound are as described respectivelyin the step a) in the embodiment 1. Moreover, in the case in which thepolymerization initiator represented by the general formula (2) is used,the polymerization initiator has a hydrocarbon structure within themolecule, and therefore an aromatic hydrocarbon is preferably used as apolymerization solvent. Specific examples of the hydrocarbons are alsoas described in the step a) in the above-described embodiment.

[Step b′)]

The step b′) is a step of reacting the compounds obtained in the stepa′) and represented by the general formulas (12) and/or (13) with thecompound represented by the following general formula (5). Through thestep b′), the compounds represented by the general formulas (14) and(15) can be obtained.R⁴(OR⁵)_(k)L  (5)

The reaction of the step b′) may be performed in the same manner as inthe step b) in the embodiment 1. That is to say, the method for addingthe compound represented by the general formula (5) to the reactionsystem, the kind and amount of the solvent used, the kind and amount ofthe basic catalyst used, the kind and amount of alkaline adsorbent used,the reaction temperature, and crystallization, washing, and purificationof the obtained compounds represented by the general formulas (14)and/or (15) may appropriately be selected within the range as describedin the step b) in the above-described embodiment.

[Step c′)]

In the step c′), the compounds obtained in the step b′) and representedby the general formulas (14) and/or (15) are deprotected. Thedeprotection is preferably performed without using a heavy metalcatalyst. More preferably, the compounds represented by the generalformulas (14) and/or (15) are deprotected under an acidic condition.Specifically, the compounds represented by the general formulas (14)and/or (15) are reacted with water or an alcohol (R⁶OH: wherein R⁶represents a hydrocarbon group having 1 to 5 carbon atoms) in thepresence of an acid catalyst, so that the conversion to the compoundsrepresented by the general formulas (3) and/or (4) may be performed. Thereaction may be performed by reacting the compounds represented by thegeneral formulas (14) and/or (15) with water or an alcohol in thepresence of an acid catalyst without a solvent or in a proper solvent asneeded. In the reaction, the yield rate can be improved by transferringthe equilibrium to the product side, and therefore produced (R¹)₃SiOH or(R¹)₃SiOR⁶ is preferably distilled away under heating or reducedpressure. The amount of water or the alcohol used is, for example, 2 to4000 equivalents, preferably 10 to 3000 equivalents, more preferably 20to 2000 equivalents, relative to the number of moles of the compoundsrepresented by the general formulas (14) and/or (15), although this isnot particularly limited thereto.H₂N—R²—(OR⁵)_(n+m)—OR⁴  (3)H₂N—R³—(OR⁵)_(n)—OR⁴  (4)

Specific examples of the acid catalyst used include carboxylic acidssuch as formic acid, acetic acid, propionic acid, succinic acid, citricacid, tartaric acid, fumaric acid, malic acid, and trifluoroacetic acid,inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, and perchloric acid, and sulfonic acids such asbenzenesulfonic acid and p-toluenesulfonic acid, and solid acids such asAMBERLYST SERIES made by Organo Corporation, although this is notlimited thereto. The amount of the acid catalyst used is, for example,0.01 to 500 equivalents, preferably 0.1 to 300 equivalents, morepreferably 0.1 to 150 equivalents, relative to the number of moles ofthe compounds represented by the general formulas (14) and/or (15).These acid compounds may be used alone, or in combinations of two ormore. In that case, the mixing ratio is not particularly limited.

Crystallization, washing, and purification of the compounds obtainedafter deprotection and represented by the general formulas (3) and/or(4) may appropriately be selected and performed within the range asdescribed in the step c) in the embodiment 1.

Since the amino group in the compounds represented by the generalformulas (3) and/or (4) is obtained by deprotection in the step c′),by-products (compounds represented by the following (A) to (C-2)) thatcan be produced by the method described in, for example, Japanese PatentNo. 3562000 are not produced, and finally narrowly distributed andhigh-purity polyalkylene glycol derivatives having an amino group at anend and represented by the general formulas (3) and/or (4) can besynthesized in the present invention. In contrast, in the case in whichthe method described in, for example, Japanese Patent No. 3562000 isused, a PEG derivative represented by the following general formula (A)cannot be prevented, as described above. Moreover, there is apossibility that secondary and tertiary amines represented by thefollowing general formulas (B-1), (B-2), (C-1), and (C-2) areby-produced in the hydrogen reduction step. It is difficult tocompletely control these side reactions by the conventional methods asdescribed above.H—(OR⁵)_(n)—OR⁴  (A)HN

R²—(OR⁵)_(n+m)—OR⁴)₂  (B-1)N

R²—(OR⁵)_(n+m)—OR⁴)₃  (B-2)HN

R³—(OR⁵)_(n)OR⁴)₂  (C-1)N

R³—(OR⁵)_(n)—OR⁴)₃  (C-2)(In the general formulas (A), (B-1), (B-2), (C-1), and (C-2), R², R³,R⁴, R⁵, m, and n are the same as defined in the general formulas (3) and(4).)[Post-Treatment Step]

The post-treatment step of purifying the compounds represented by thegeneral formulas (3) and/or (4) with a strong acid cation exchange resinmay be performed after the step c′). The post-treatment step in thiscase may also be performed by the same operations as described in thepost-treatment step in the embodiment 1.

In this way, the steps a′) to c′) are performed, (or the pre-steps 1′and 2′ and/or the post-treatment step are further performed optionallybefore and/or after performing the steps a′) to c′)), so that thecompounds (narrowly distributed and high-purity polyalkylene glycolderivatives having an amino group at an end) represented by the generalformulas (3) and/or (4) can be produced.

That is to say, according to another aspect, the present inventionrelates to narrowly distributed and high-purity polyalkylene glycolderivatives having an amino group at an end, the polyalkylene glycolderivatives obtained by the above-described production method andrepresented by the general formulas (3) and/or (4).

Regarding properties of the compound represented by the general formulas(3) and/or (4) obtained after performing the steps a′) to c′) (orobtained by further performing the pre-steps 1′ and 2′ and/or thepost-treatment step optionally before and/or after performing the stepsa′) to c′)), namely the dispersity and weight average molecular weight,the amount of by-products (PEG derivative, and secondary and tertiaryamines) mixed, the content of heavy metal impurities are the same asdescribed with respect to the compound represented by the generalformula (III) in the embodiment 1.

According to yet another aspect, the present invention relates to ametal salt of a protected amino group-containing alcohol compoundrepresented by the general formula (I), the compound used as apolymerization initiator for use in the above-disclosed method forproducing a polyalkylene glycol derivative having an amino group at anend. Among others, the metal salt is preferably a metal salt of a novelsilyl-protected amino group-containing alcohol compound represented bythe general formula (1) or (2). Further, the present invention alsorelates to a novel protected amino group-containing alcohol compoundrepresented by the general formula (i), the compound used as a rawmaterial (starting material) of the polymerization initiator. Amongothers, the alcohol compound is preferably a novel silyl-protected aminogroup-containing alcohol compound represented by the general formula (6)or (7). The definition, production method, and use method of thesecompounds are described in detail in the method for producing apolyalkylene glycol derivative in the embodiment 1 and the embodiment 2,and therefore the descriptions thereof are omitted.

EXAMPLES

The present invention is specifically illustrated with reference to thefollowing Examples and Comparative Examples, though the presentinvention is not limited to the following Examples. In the notation ofmolecular weight in Examples, the weight average molecular weight (Mw)and the number average molecular weight (Mn) are values in terms ofpolyethylene glycol measured by GPC. Measurement by gel permeationchromatography (GPC) was performed under the following conditions:

Column: TSK gel Super AWM-H, Super AW-3000

Developing solvent: DMF (0.01 mol/L lithium bromide solution)

Column oven temperature: 60° C.

Sample concentration: 0.20 wt. %

Sample injection volume: 25

Flow rate: 0.3 ml/min

[Synthesis Example 1] Synthesis of Compound Represented by Formula (iA)[Synthesis Example 1-1] Synthesis of Compound Represented by Formula(iA-1)

In a 50 ml three neck flask, 0.75 g of 2-(3-aminopropoxy)-ethanol, 2.35g of triethylamine, and 2.92 g of toluene were charged, and then 5.98 gof triethylsilyl trifluoromethanesulfonate (hereinafter, written as“TESOTf”) was dripped under a nitrogen atmosphere. Stirring was thenperformed at 80° C. for 25 hours. The reaction liquid was transferredinto a separatory funnel, the lower layer was separated, and the upperlayer was distilled under reduced pressure, so that 2.71 g (yield rate93.3%) of a silyl-protected compound (iA-1) was produced.

Silyl-protected compound (iA-1)

Colorless liquid

Boiling point 190° C./10 Pa

¹H-NMR (500 MHz, CDCL3): δ=0.63 (18H, q), 0.96 (27H, t), 1.69 (2H, m),2.83 (2H, m), 3.40 (2H, t), 3.49 (2H, t), 3.76 (2H, t)

In the formula, TES means a triethylsilyl group.

[Synthesis Example 1-2] Synthesis of Compound Represented by Formula(iA)

In a 10 ml round-bottom flask, 2.21 g of the silyl-protected compound(iA-1), 2.70 g of methanol, and 13 mg of sodium methoxide were charged,and stirring was performed at 60° C. for 18 hours. Triethylmethoxysilane was then distilled away under reduced pressure, 2.70 g ofmethanol was again placed into the flask, and stirring was performed at60° C. The same operation was repeated, quenching was performed withsodium bicarbonate after completion of reaction, solvent substitutionwith toluene was performed, and a salt was then removed by filtration.Reduced pressure-distillation was then performed, so that 1.50 g (yieldrate 90.0%) of a silyl-protected amino group-containing alcohol (iA) wasproduced. The measured water content ratio after distillation was 1 ppmor less.

Silyl-protected amino group-containing alcohol (iA)

Colorless liquid

Boiling point 118 to 122° C./10 Pa

¹H-NMR (500 MHz, CDCL3): δ=0.60 (12H, q), 0.93 (18H, t), 1.68 (2H, m),1.96 (1H, bs), 2.82 (2H, m), 3.40 (2H, t), 3.50 (2H, m), 3.73 (2H, m)

[Synthesis Example 2] Synthesis of Formula (iA) by Another Method[Synthesis Example 2-1] Synthesis of Electrophile (iiA)

(2-1-1) Synthesis of Silyl Protector (iiA-1)

In a 300 ml three neck flask, 6.0 g of 3-amino-1-propanol, 28.74 g oftriethylamine, and 18.0 g of toluene were charged, and then 75.0 g ofTESOTf was dripped therein under a nitrogen atmosphere. Stirring wasthen performed at 80° C. for 25 hours. The reaction liquid wastransferred into a separatory funnel, the lower layer was separated, andthe upper layer was distilled under reduced pressure, so that 31.47 g(yield rate 93.3%) of a silyl protector (iiA-1) was produced.

Silyl Protector (iiA-1)

Colorless liquid

Boiling point 133 to 138° C./10 Pa

¹H-NMR (500 MHz, CDCL3): δ=0.60 (18H, q), 0.94 (27H, t), 1.62 (2H, m),2.83 (2H, m), and 3.54 (2H, t)

(2-1-2) Silyl-Protected Amino Group-Containing Alcohol (iiA-2)

In a 200 ml round-bottom flask, 30.98 g of silyl protector (iiA-1),30.98 g of methanol, and 0.2 g of sodium methoxide were charged, andstirring was performed at 60° C. for 18 hours. Triethylmethoxy silanewas then distilled under reduced pressure, 30.98 g of methanol was againplaced into the flask, and stirring was performed at 60° C. The sameoperation was repeated, quenching was performed with sodium bicarbonateafter completion of reaction, solvent substitution with toluene wasperformed, and a salt was then removed by filtration. Toluene was thendistilled away under reduced pressure, so that 22.66 g of asilyl-protected amino group-containing alcohol (iiA-2) was produced(crude yield rate 96.4%). It was able to be confirmed from a ¹H-NMRspectrum that this crude product had a sufficient purity as anintermediate, so that the compound (iiA-2) was directly used in thesubsequent step.

Silyl-protected amino group-containing alcohol (iiA-2)

Colorless liquid

¹H-NMR (500 MHz, CDCL3): δ=0.60 (12H, q), 0.93 (18H, t), 1.67 (2H, m),2.85 (2H, m), and 3.59 (2H, m)

(2-1-3) Synthesis of Electrophile (iiA)

In a 50 ml three neck flask, 4.7 g of TsCl, 5 g of methylene chloride,and 5.0 g of triethylamine were charged, and a solution of 5.0 g of thesilyl-protected amino group-containing alcohol (iiA-2) dissolved in 10.0g of methylene, chloride was dripped therein while the flask wasice-cooled. The temperature was brought back to normal temperature,stirring was performed for 13 hours, quenching was then performed withwater, and extraction was performed with toluene. The toluene solutionwas then concentrated, so that 7.6 g (crude yield rate 100%) of anelectrophile (iiA) was produced. It was confirmed from a ¹H-NMR spectrumthat the crude product had a sufficient purity as an intermediate, andthus (iiA) was used directly for the subsequent step.

Electrophile (iiA)

Brown liquid

¹H-NMR (500 MHz, CDCL₃): δ=0.54 (12H, q), 0.89 (18H, t), 1.68 (2H, m),2.45 (3H, s), 2.71 (2H, m), and 3.98 (2H, t)

[Synthesis Example 2-2] Synthesis of Electrophile (iiB)

In a 200 ml three neck flask, 15.93 g of 3-bromopropylaminehydrobromate, 27.26 g of triethylamine, and 47.79 g of toluene werecharged, and 50.00 g of TESOTf was then dripped therein under a nitrogenatmosphere. Stirring was then performed at 80° C. for 63 hours. Thereaction solution was transferred to a separatory flask, the lower layerwas separated, and the upper layer was distilled under reduced pressure,so that 8.00 g of an electrophile (iiB) was produced (yield rate 30.0%).

Electrophile (iiB)

Colorless liquid

Boling point 108° C./30 Pa

¹H-NMR (500 MHz, CDCL₃): δ=0.61 (12H, q), 0.94 (18H, t), 1.92 (2H, m),2.90 (2H, m), and 3.31 (2H, t)

[Synthesis Example 2-3] Synthesis of Compound Represented by Formula(iA) with Electrophile (iiA)

In a 100 ml three neck flask, 6.78 g of ethylene glycol, 10 g ofN-methylpyrrolidone, and 1.35 g of potassium tert-butoxide were charged,stirring was performed for 30 minutes, and then a solution of 5.0 g ofan electrophile (iiA) dissolved in 15 g of N-methylpyrrolidone wasdripped at normal temperature. After the temperature was raised to 60°C. and stirring was performed for 5 hours, the reaction was stopped with0.18 g of sodium bicarbonate. Subsequently, solvent substitution withdiphenyl ether was performed, and a precipitated salt was then removedby filtration. Reduced pressure-distillation was then performed, so that3.16 g (yield rate 65.7%) of a silyl-protected amino group-containingalcohol (iA) was produced. The measured water content ratio afterdistillation was 1 ppm or less (Measurement of the water content ratiowas performed by a Karl Fisher moisture meter, and the same applieshereinafter).

Silyl-protected amino group-containing alcohol (iA)

Colorless liquid

Boiling point: same as the result obtained in the [Synthesis Example1-2].

¹H-NMR (500 MHz, CDCL3): same as the result obtained in the [SynthesisExample 1-2].

In the formula, Ts means a para-toluenesulfonyl group, t-BuOK meanstert-butoxide, and NMP means N-methylpyrrolidone.

[Synthesis Example 2-4] Synthesis of Compound Represented by Formula(iA) with Electrophile (iiB)

In a 200 ml three neck flask, 2.98 g of ethylene glycol, 5.0 g ofN-methylpyrrolidone, and 0.54 g of potassium tert-butoxide were charged,stirring was performed for 30 minutes, and then a solution of 2.00 g ofan electrophile (iiB) dissolved in 10.0 g of N-methylpyrrolidone wasdripped at normal temperature. After the temperature was raised to 60°C. and stirring was performed for 5 hours, the reaction was stopped with0.08 g of sodium bicarbonate. Subsequently, solvent substitution withdiphenyl ether was performed, and a precipitated salt was then removedby filtration. Reduced pressure-distillation was then performed, so that1.07 g (yield rate 64.0%) of a silyl-protected amino group-containingalcohol (iA) was produced. The measured water content ratio afterdistillation was 1 ppm or less.

Silyl-protected amino group-containing alcohol (iA)

Colorless liquid

Boiling point: same as the result obtained in the [Synthesis Example1-2].

¹H-NMR (500 MHz, CDCL3): same as the result obtained in the [SynthesisExample 1-2].

[Synthesis Example 3] Synthesis of Compound Represented by Formula (iB)[Synthesis Example 3-1] Synthesis of Compound Represented by Formula(iB-1)

In a 200 ml three neck flask, 5.00 g of 6-amino-1-hexanol, 15.68 g oftriethylamine, and 15.00 g of toluene were charged, and then 40.91 g ofTESOTf was dripped under nitrogen atmosphere. Stirring was thenperformed at 80° C. for 25 hours. The reaction liquid was transferredinto a reparatory funnel, the lower layer was separated, and the upperlayer was distilled under reduced pressure, so that 18.39 g (yield rate93.0%) of a silyl-protected compound (iB-1) was produced.

Silyl-protected compound (iB-1)

Colorless liquid

Boiling point 180° C./10 Pa

¹H-NMR (500 MHz, CDCL3): 8=0.63 (18H, q), 0.96 (27H, t), 1.69 (8H, m),2.83 (2H, m), 3.40 (2H, t)

[Synthesis Example 3-2] Synthesis of Compound Represented by Formula(iB)

In a 50 ml one neck flask, 5.00 g of the silyl-protected compound(iB-1), 5.00 g of methanol, and 29 mg of sodium methoxide were charged,and stirring was performed at 60° C. for 18 hours. Triethylmethoxysilane was then distilled away under reduced pressure, 5.00 g ofmethanol was again placed into the flask, and stirring was performed at60° C. The same operation was repeated, then quenching was performedwith sodium bicarbonate after completion of reaction, solventsubstitution with toluene was performed, and then a salt was removed byfiltration. Reduced pressure-distillation was then performed, so that3.35 g of a silyl-protected amino group-containing alcohol (iB) wasproduced (yield rate 89.0%). The measured water content ratio afterdistillation was 1 ppm or less.

Silyl-protected amino group-containing alcohol (iB)

Colorless liquid

Boiling point 118 to 112° C./10 Pa

[NMR4]

[Synthesis Example 4] Synthesis of Compound Represented by Formula (IA)[Synthesis Example 4-1] Synthesis of Compound Represented by Formula(IA)

In a glove box under a nitrogen atmosphere, potassium hydride (in amineral oil form, made by Kanto Chemical Co., Ltd.) was fed into a 50 mLthree neck flask, and after the mineral oil was washed with hexane to beseparated, vacuum drying was performed for about two hours to obtain0.50 g (12.5 mmol) of potassium hydride. Into the flask, 7.71 g ofdistilled THF was added with a syringe, and 4.44 g (12.8 mmol) of thecompound represented by the general formula (iA) was dripped at normaltemperature. Stirring was performed at normal temperature for 1 hour andthen at 50° C. for 2 hours, so that 12.40 g (1.02 mmol/g) of a THFsolution of the compound represented by the general formula (IA) wasproduced. Precipitation of a salt and cloudiness were not observed atthat time ((IA) mass/THF solution mass=39.8 wt. %). The ratio of theamounts of substances between the polymerization initiator (IA)synthesized by the above-described reaction and the alcohol (iA) that isan initiator raw material is 98:2 (mol %). A reaction scheme is shown inthe following.

[Synthesis Example 4-2] Synthesis of Compound Represented by Formula(IA) by Another Method

In a glove box under a nitrogen atmosphere, 2.02 g of naphthalene and0.68 g of potassium were weighed and fed into a 100 mL three neck flask,and vacuum drying was performed for 1 hour. The flask was then broughtback to under a nitrogen atmosphere, 19.65 g of distilled THF was addedinto the flask with a syringe. Stirring was performed for 1 hour toprepare a THF solution of potassium naphthalene (0.71 mmol/g). On theother hand, 1.96 g (5.64 mmol) of the compound represented by theformula (iA) was weighed with a syringe and fed into a 50 ml three neckflask under a nitrogen atmosphere. 7.85 g of the THF solution ofpotassium naphthalene prepared above was dripped therein at normaltemperature. Maturation was performed for 1 hour, so that 9.77 g (0.58mmol/g) of a THF solution of the polymerization initiator (IA) wasproduced. Precipitation of a salt and cloudiness were not observed atthat time ((IA) mass/THF solution mass=22.3 wt. %). The ratio of theamounts of substances between the polymerization initiator (IA)synthesized by the above-described reaction and the alcohol (iA) that isan initiator raw material is 98:2 (mol %). A reaction scheme is shown inthe following.

[Synthesis Example 5] Synthesis of Compound Represented by Formula(I-1A)

A stirring bar was placed in a 500 mL four neck flask connected to athermometer, a dripping funnel, and a Dimroth condenser. After thedegree of vacuum in the device was held at 10 Pa or less, the internalpart of the device was heated with an oil bath and a heat gun, so thatthe water content in the system was removed. Subsequently, 1.69 g of theTHF solution of the compound represented by the formula (IA), the THFsolution prepared in the [Synthesis Example 4-1] and 140 g of distilledTHF were added into the 2 L four neck flask under nitrogen stream. Intothe dripping funnel, 20 g of ethylene oxide and 40 g of distilled THFwere injected, to be dripped into the 500 mL four neck flask slowly.After confirming stabilization of the temperature in the 500 mL fourneck flask, maturation was performed at 45 to 50° C. for 8 hours. Areaction scheme is shown in the following.

After completion of the reaction, the oil bath was detached and thereaction system was cooled to room temperature. A small amount of theproduced reaction liquid was sampled, and the reaction was stopped withacetic acid for measurement by GPC. The following results were obtained:Mw=8,000 and Mw/Mn=1.04.

[Synthesis Example 6] Synthesis of Compound Represented by Formula (IIA)[Synthesis Example 6-1] Synthesis of Compound Represented by Formula(IIA)

In a reaction liquid of the compound represented by the formula (I-1A),2.41 g of 2-bromoethylmethyl ether and 10.5 mL (1 mol/L) of a THFsolution of potassium tert-butoxide were added, and stirring wasperformed for 5 hours under refluxing. After a salt in the reactionliquid was removed by filtration, the reaction liquid was concentratedto 25 wt. %, and the concentrated liquid was transferred into a drippingfunnel. In a 500 mL beaker with a stirring bar therein, 201 g of hexanewas placed, and after dripping of the concentrated liquid thereto for 10minutes, maturation was performed for 20 minutes. The produced whitepowder was filtered and then returned to the original beaker, to bewashed with 99 g of hexane for 20 minutes, and the same washingoperation was further performed once. A reaction scheme is shown in thefollowing.

The produced white powder was vacuum-dried to obtain 18.6 g of a polymer(IIA). The following GPC measurement results were obtained: Mw=8,000 andMw/Mn=1.05.

[Synthesis Example 6-2] Synthesis of Compound Represented by Formula(IIA) by Another Method

In the reaction liquid of the compound represented by the formula(I-1A), 2.05 g of 2-methoxyethyl-p-toluenesulfonate and 0.50 g ofpotassium tert-butoxide were added, and stirring was performed at 40° C.for 5 hours. After a salt in the reaction liquid was removed byfiltration, the reaction liquid was concentrated to 25 wt. %, and theconcentrated liquid was transferred to a dripping funnel. In a 500 mLbeaker with a stirring bar therein, 200 g of hexane was placed, andafter dripping of the concentrated liquid thereto for 10 minutes,maturation was performed for 10 minutes. The produced white powder wasfiltered and then returned to the original beaker, to be washed with 100g of hexane for 10 minutes, and the same washing operation was furtherperformed once. A reaction scheme is shown in the following.

The produced white powder was vacuum-dried to obtain 18.6 g of thepolymer (IIA). The following GPC measurement results were obtained:Mw=8,000 and Mw/Mn=1.05.

[Synthesis Example 6-3] Synthesis of Compound Represented by Formula(IIA) by Yet Another Method

A 2 L high pressure reaction vessel was dried by nitrogen purge, and8.29 g (1.02 mmol/g, 8.46 mmol) of a THF solution of the polymerizationinitiator (IA) synthesized by the method of the above-described[Synthesis Example 4-1] and 885 g of distilled THF were added theretounder a nitrogen atmosphere. After the temperature in the vessel wasraised to 45° C., 100 g of ethylene oxide was continuously charged intothe reaction vessel, and the pressure in the system was then adjusted to0.15 MPa by nitrogen pressurization. Stirring was performed at 45° C. togradually lower the pressure of the system, and after 6 hours, thepressure of the system became stable at 0.11 MPa where the reaction wasdetermined to be completed. After the reaction system was cooled to 40°C., 9.75 g of 2-methoxyethyl-p-toluenesulfonate as an electrophile wasdissolved in 97.5 g of THF, and the resultant mixture was charged intothe system, and, further, 21 ml of a THF solution of potassiumtert-butoxide (1 mol/L) was diluted with 21 g of THF, and the resultantsolution was charged into the system. Subsequently, with the temperaturebeing held at 40° C., maturation was performed for 5 hours. Aprecipitated salt was separated by filtration, 17 g of an adsorptionmaterial KW-2000 was added to the filtrate, stirring was performed for 2hours, and the adsorption material was then removed by filtration. Thereaction solution was concentrated to 400 g. 750 g of hexane and 750 gof ethyl acetate were then placed in a 3 L beaker with a stirring bartherein, and after dripping the produced reaction solution, maturationwas performed for 10 minutes. The produced white powder was filtered andthen returned to the original beaker, to be washed with 375 g of hexaneand 375 g of ethyl acetate for 10 minutes, and after the same washingwas repeated once again, the produced white powder was vacuum-dried toobtain 96 g of the polymer (IIA). The following GPC measurement resultswere obtained: Mw=11,400 and Mw/Mn=1.03. A reaction scheme is shown inthe following.

It is revealed that the polymerization with ethylene oxidestoichiometrically progresses in the Synthesis Example 6-3 as shown inTable 1 below.

TABLE 1 Yield rate Theoretical Mw Mw Mw/Mn (%) Synthesis Example 6-312,000 11,400 1.03 95.5

[Synthesis Example 7] Synthesis of Compound Represented by Formula(IIIA-a) [Synthesis Example 7-1] Synthesis of Compound Represented byFormula (IIIA-a)

Into a 50 ml three neck flask, 1.0 g of the compound produced in the[Synthesis Example 6-1] and represented by the formula (IIA), 9.0 g ofTHF and 0.4 ml of 1N HCl aq. were fed, and stirring was performed at 40°C. for 4 hours. The reaction was then stopped with 0.2 ml of 25 wt. %NaOH aqueous solution. After the reaction solution was concentrated todistill away water, the concentration of the polymer solution wasadjusted by adding 5.7 g of THF, and a precipitated salt was filtered.In a 100 mL beaker with a stirring bar therein, 10 g of hexane wasplaced, and after dripping the produced reaction solution, maturationwas performed for 10 minutes. The produced white powder was filtered andthen returned to the original beaker, to be washed with 5 g of hexanefor 10 minutes, and the same washing operation was further performedonce.

The produced white powder was vacuum-dried to obtain 0.7 g of a compoundrepresented by the formula (IIIA-a). The following GPC measurementresults were obtained: Mw=7,900 and Mw/Mn=1.05. A reaction scheme isshown in the following.

Deprotection may subsequently be performed by adding hydrochloric acidwithout purifying the compound represented by the formula (IIA) afterthe reaction, and in that case, the process can be further simplified.

[Synthesis Example 7-2] Synthesis of Compound Represented by Formula(IIIA-a) by Another Method

Into a 1 L three neck flask, 100 g of the polymer (IIA) produced in the[Synthesis Example 6-3], 400 g of MeOH, and 5.00 g of acetic acid werefed, and stirring was performed at 35° C. for 3 hours. The reaction wasthen stopped with 24.12 g of a 28% solution of sodium methylate inmethanol. The reaction solution was concentrated, and solventsubstitution with toluene was performed, so that 450 g of a polymersolution was prepared, and a precipitated salt was filtered. To theproduced polymer solution, 100 g of the adsorption material KW-2000 wasadded, and treatment was performed at 35° C. for 1 hour to remove thetrace amount of the salt. In a 3 L beaker with a stirring bar therein,1000 g of hexane and 500 g of ethyl acetate were placed, and afterdripping the produced reaction solution, maturation was performed for 10minutes. The produced white powder was filtered and then returned to theoriginal beaker, to be washed with 600 g of hexane and 300 g of ethylacetate for 10 minutes, and the same washing operation was furtherperformed once.

The produced white powder was vacuum-dried to obtain 90 g of a polymer(IIIA-a). The following GPC measurement results were obtained: Mw=11,000and Mw/Mn=1.03. A reaction scheme is shown in the following.

[Synthesis Example 8] Synthesis of Compound Represented by Formula(IIIB-a)

A compound represented by the formula (IIIB-a) was produced by the sameoperations as in [Synthesis Examples 4 to 7], except that the compoundrepresented by the formula (iA) was changed to the compound representedby the formula (iB). That is to say, the polymerization initiator (IB)was synthesized using the compound represented by the formula (iB) bythe same operations as in the [Synthesis Example 4-1], and the compoundrepresented by the formula (IIIB-a) was produced with the polymerizationinitiator by the same operations as in the [Synthesis Examples 5 to 7].In addition, the same operations as in the [Synthesis Examples 6-1 and7-1] were performed in the [Synthesis Examples 6 and 7] respectively.The following GPC measurement results were obtained for the compoundrepresented by the formula (IIIB-a): Mw=7,900 and Mw/Mn=1.05. A reactionscheme is shown in the following.

[Synthesis Example 9] Synthesis of Compounds Represented by Formulas(IIIA-b) to (IIIA-f)

Polymers (IIIA-b) to (IIIA-f) were synthesized by approximately the sameoperations as in the [Synthesis Examples 4 to 7], except that the ratiobetween the compound represented by the formula (iA) and ethylene oxidewas changed. In addition, the same operations as in the [SynthesisExamples 4-1, 6-1, and 7-1] were performed in the [Synthesis Examples 4,6, and 7] respectively. The analysis results are shown in Table 2.

TABLE 2 Formula Ethylene oxide (iA) (mmol) (g) Mw Mw/Mn IIIA-a 1.72 207,900 1.05 IIIA-b 1.72 22 8,600 1.05 IIIA-c 1.72 25 9,800 1.05 IIIA-d1.72 30 12,000 1.04 IIIA-e 1.72 38 15,200 1.04 IIIA-f 1.72 50 19,8001.05

[Synthesis Example 10] Synthesis of Compounds Represented by Formulas(IIIB-b) to (IIIB-f)

Polymers (IIIB-b) to (IIIB-f) were synthesized by approximately the sameoperations as in the [Synthesis Example 8], except that the ratiobetween the compound represented by the formula (iB) and ethylene oxidewas changed. The analysis results are shown in Table 3.

TABLE 3 Formula Ethylene oxide (iB) (mmol) (g) Mw Mw/Mn IIIB-a 1.72 207,900 1.05 IIIB-b 1.72 22 8,600 1.05 IIIB-c 1.72 25 9,900 1.05 IIIB-d1.72 30 12,200 1.04 IIIB-e 1.72 38 15,300 1.04 IIIB-f 1.72 50 19,7001.05

[Synthesis Example 11] Synthesis of compounds represented by formulas(IIIA-g) to (IIIA-l), and (IIIB-g) to (IIIB-l)

Compounds represented by the formulas (IIIA-g) to (IIIA-l) weresynthesized by approximately the same operations as in the [SynthesisExamples 4 to 7], and compounds represented by the formulas (IIIB-g) to(IIIB-l) were synthesized by approximately the same operations as in the[Synthesis Example 8], except that 2-bromoethylmethyl ether as thesubstrate in the [Synthesis Example 6-1] was changed to 2-bromoethyl(substituted) alkyl ethers having an alkyl group (R⁴) (with asubstituent) at an end, the ethers shown in the table below. The sameoperations as in the Synthesis Examples 4-1, 6-1, and 7-1 were performedin the Synthesis Examples 4, 6, and 7 respectively. The analysis resultsare shown in Tables 4 and 5.

TABLE 4 R⁴ Mw Mw/Mn IIIA-g Ethyl group 8,000 1.05 IIIA-h n-Propyl group8,100 1.06 IIIA-i Isopropyl group 8,200 1.04 IIIA-j n-Butyl group 8,4001.05 IIIA-k Cyanoethyl group 8,400 1.05 IIIA-l Methacryloyloxyethylgroup 8,500 1.05

TABLE 5 R⁴ Mw Mw/Mn IIIB-g Ethyl group 7,900 1.05 IIIB-h n-Propyl group8,000 1.05 IIIB-i Isopropyl group 8,100 1.04 IIIB-j n-Butyl group 8,3001.05 IIIB-k Cyanoethyl group 8,300 1.05 IIIB-l Methacryloyloxyethylgroup 8,400 1.05

[Synthesis Example 12] Purification of the Compound Represented by theFormula (IIIA-a)

The inside of a cartridge filled with 50 g of a cation exchange resinDIAION PK-208 (made by Mitsubishi Chemical Corporation) was washed with300 g of 1N hydrochloric acid, and then washed 3 times with 300 g ofion-exchanged water, and subsequently once with 300 g of methanol. Intoa 500 mL two neck flask, a 5 wt. % solution of the polymer (IIIA-a) inmethanol (polymer content; 10 g) was injected, and transferred into thecartridge with a pump. The methanol solution discharged from the liquidoutlet of the cartridge was added into the original 500 mL round-bottomflask. The operation was continuously performed for 2 hours, so that thepolymer (IIIA-a) was adsorbed to the cation exchange resin. Subsequentlythe resin in the cartridge was washed with 300 g of methanol once, andthen the polymer (IIIA-a-2) was eluted from the cation exchange resinwith 50 g of 7N ammonia solution (methanol solution made by KantoChemical Co., Ltd.). The purified polymer after the process of elutionfrom the cation exchange resin is denoted as (“IIIA-a-2”).

On the other hand, even when the compound represented by the formula(IIa) is used in place of the compound represented by the formula(IIIA-a), deprotection progresses in the methanol solution in thepresence of the cation exchange resin catalyst, and therefore bothdeprotection and purification can be performed in parallel, and theprocess was able to be further simplified.

The produced eluent was transferred into a 500 mL round-bottom flask,and ammonia and methanol were distilled away with a rotary evaporator.Through vacuum concentration almost to dryness, the solvent wassubstituted with toluene such that the solid content concentration ofthe polymer (IIIA-a-2) was adjusted to 25 wt. %.

In a 500 mL beaker with a stirring bar therein, 100 g of hexane and 50 gof ethyl acetate were mixed. After dripping of a 25 wt. % producedpolymer (IIIA-a-2) solution for 10 minutes with a dripping funnel,stirring was performed for 20 minutes, and maturation was performed. Theproduced white powder was filtered and then returned to the originalbeaker, to be washed with a mixed solvent of 50 g of hexane and 25 g ofethyl acetate for 20 minutes. The same washing operation was furtherperformed once.

The produced white powder was vacuum-dried to obtain 8.51 g of a polymer(IIIA-a-2). The following GPC measurement results were obtained:Mw=8,000 and Mw/Mn=1.05. On the other hand, in the case in which thereaction was performed in the same manner as in the above-describedExample, except that a small amount of water was purposely mixed duringpolymerization, an extremely small amount of a by-product represented bythe following formula (Villa) produced due to water that was mixedduring polymerization was able to be confirmed by H-NMR in the compoundproduced through concentration and drying of a filtrate obtained by thepurification with a cation exchange resin. From the above fact, even ifwater is mixed during polymerization, a by-product was able to beremoved with a cation exchange resin and a production margin was able tobe enlarged.

[Comparative Synthesis Example 1] Synthesis of Polymer (VIa)

A stirring bar and 71 mg (1.01 mmol) of potassium methoxide (made byKanto Chemical Co., Ltd.) as a polymerization initiator was placed in a500 mL four neck round-bottom flask connected to a thermometer, adripping funnel, and a Dimroth condenser. After the degree of vacuum inthe device was held at 10 Pa or less, the internal part of the devicewas heated with an oil bath and a heat gun, so that the water content inthe system was removed.

Subsequently 40 μL (1.00 mmol) of methanol (made by Tokyo ChemicalIndustry Co., Ltd.) and 140 g of distilled THF were injected in the fourneck flask under a nitrogen stream, and the mixture was stirred at roomtemperature until potassium methoxide was completely dissolved. Theratio of the amounts of substances between potassium methoxide being thepolymerization initiator synthesized by the above-described method andmethanol being the alcohol that is an initiator raw material is 50:50(mol %).

Into the dripping funnel, a mixed solution of 35 g of ethylene oxide and60 g of distilled THF were injected, to be dripped into the four neckflask slowly, with the inner temperature being kept at 35° C. or lower.After dripping of the entire quantity, the mixture was stirred for 80hours, with the inner temperature being kept at 50° C. or lower.

After confirming no change in conversion ratio of ethylene oxide, 0.06 gof acetic acid was added into the flask. After removal of ethylene oxideby nitrogen bubbling, the reaction liquid was transferred into a 500 mLround-bottom flask and was concentrated with a rotary evaporator untilsolid precipitated. The crude product of polymer in an amount of 23 gwas redissolved in 46 g of toluene, and transferred into a drippingfunnel.

Into a 500 mL beaker with a stirring bar therein, 138 g of isopropylalcohol was injected. After dripping of the polymer solution for 10minutes with a dripping funnel, maturation was performed for 20 minutes.The produced white powder was filtered and returned to the originalbeaker, to be washed with a mixed solvent of 69 g of isopropyl ether for20 minutes. And the same washing operation was further performed twice.A reaction scheme is shown in the following.

The produced white powder was vacuum-dried to obtain 18.54 g of acomparative polymer (VIa). The following GPC measurement results wereobtained: Mw=7,200 and Mw/Mn=1.16.

[Comparative Synthesis Example 2] Synthesis of Polymer (IXa)

In a 300 ml four neck flask, 10.00 g of the polymer (VIa), 29.5 g ofTHF, 0.56 g of 10 wt. % potassium hydroxide aqueous solution, 0.5 g ofH₂O, and 1.06 g of acrylonitrile were charged, and stirring wasperformed at normal temperature for 6 hours. After completion ofreaction, 1.45 g of an alkaline adsorbent “TOMITA AD 700NS” (productname, synthesized aluminum silicate made by Tomita Pharmaceutical Co.,Ltd.) was added, and reaction was performed for 2 hours. Afterfiltration of the alkaline adsorbent, the filtrate was transferred intoa 300 mL round-bottom flask, solvent substitution with toluene wasperformed, and concentration was performed to a solid contentconcentration of a comparative polymer (IXa) of 25 wt. %.

In a 500 mL beaker with a stirring bar therein, 100 g of hexane and 50 gof ethyl acetate were mixed. After dripping of the concentrated liquidfor 10 minutes with a dripping funnel, maturation was performed for 20minutes. The produced white powder was filtered and then returned to theoriginal beaker, to be washed with a mixed solvent of 50 g of hexane and25 g of ethyl acetate for 20 minutes. The same washing operation wasfurther performed once. A reaction scheme is shown in the following.

The produced white powder was vacuum-dried to obtain 9.12 g of acomparative polymer (IXa). The following GPC measurement results wereobtained: Mw=7,300 and Mw/Mn=1.15.

[Comparative Synthesis Example 3] Synthesis of Polymer (IIIc)

Into a 500 mL autoclave for hydrogen reduction, 5.0 g of a polymer(IXa), 5.0 g of Raney cobalt catalyst R-400 (made by Nikko RicaCorporation), 45.0 g of methanol, and 3.0 mL of 1 N methanol solution ofammonia (made by Aldrich) were injected at room temperature.Subsequently, hydrogen gas (pressure: 10 kg/cm²) was provided therein,and the inner temperature was raised to 120° C. for a direct reactionfor 6 hours. After cooling to room temperature, the pressure wasreturned to atmospheric pressure. Subsequently nitrogen was injected topurge ammonia from the system. After removal of the Raney cobaltcatalyst by filtration, the filtrate was transferred into a 100 mLround-bottom flask, and ammonia and methanol were distilled away with arotary evaporator. Through vacuum concentration to dryness, 4.5 g of amixture of a polymer (IIIc) and the compounds represented by thefollowing formula (IVc) to (VIc) were obtained. The following GPCmeasurement results were obtained: Mw=7,300 and Mw/Mn=1.25. A reactionscheme and by-products are described in the following.

Analysis of Content of Impurities in Products Produced in SynthesisExamples 7-1, 8, and 12 and Comparative Synthesis Example 3

The content of impurities in the product produced in the [SynthesisExample 7-1], [Synthesis Example 8], and [Synthesis Example 12] and inthe product produced in the [Comparative Synthesis Example 3] wereanalyzed. The results are shown in Table 6 below.

A compound represented by “mPEG” in Table 6 is a compound correspondingto the general formula (VIc) in the [Comparative Synthesis Example 3]and is a compound produced through β-elimination of acrylonitrile from apolymer having a cyanoethyl group at an end. The compositional ratio ofmPEG was calculated by H-NMR measurement. First of all, each of theproducts produced in the [Synthesis Example 7-1], [Synthesis Example 8],[Synthesis Example 12], and [Comparative Synthesis Example 3] wasweighed at 10 mg, and each was dissolved in 0.75 ml of CDCl3, 50 mg oftrifluoroacetic anhydride was then added thereto, and the resultantmixture was left standing for 1 day. The compositional ratio of mPEG wascalculated from the ratio between a proton originated from α-methyleneof an ester in the compound represented by the general formula (VI-1)produced through the treatment and a proton originated from α-methyleneof an amide in the compound represented by the general formula (III-1)also produced from the treatment.

Compounds represented by “secondary and tertiary amines” in Table 6 arecompounds corresponding to the general formulas (IVc) and (Vc) in the[Comparative Polymer Synthesis Example 3] respectively. The amount ofthe compounds mixed was measured by GPC and was calculated from the areapercentages of the polymers having twice or three times as large as themolecular weight.

From these results, β-elimination of acrylonitrile and production ofsecondary and tertiary amines due to hydrogen reduction were observed inthe comparative polymer (IIIc), however these by-products were notobserved in the example polymers (IIIA-a), (IIIB-a), and (IIIA-a-2).

TABLE 6 Secondary and mPEG tertiary amines Polymer (IIIA-a) <1% <1%Polymer (IIIB-a) <1% <1% Polymer (IIIA-a-2) <1% <1% Comparative polymer(IIIc) 10%  5%

Metal Analysis of Products Produced in Synthesis Examples 7-1, 8, and12, and Comparative Synthesis Example 3

Metal impurities in the products produced in each of the [SynthesisExample 7-1], [Synthesis Example 8], and [Synthesis Example 12], and inthe product produced in the [Comparative Synthesis Example 3] wereanalyzed with a high frequency inductively coupled plasma massspectrometer (ICP-MS, Agilent Technologies 7500 cs). The analysis wasperformed by a standard loaded method using samples each obtained bydiluting each product with ultrapure water by 100 times for measurement.The analysis results (value obtained in terms of solid content) areshown in Table 7 (in units of ppb).

As a result of the metal analysis, it is revealed that the heavy metalused for reduction is mixed in the comparative polymer (IIIc), but thata heavy metal is not contained in the example polymers (IIIA-a),(IIIB-a) and (IIIA-a-2) of the Examples because a heavy metal catalystis not used in the [Synthesis Example 7-1], [Synthesis Example 8], and[Synthesis Example 12].

TABLE 7 Co Ni Pd Pt Rh Ru Cu Cr K Polymer <1 <1 <1 <1 <1 <1 <1 <1 7000(IIIA-a) Polymer <1 <1 <1 <1 <1 <1 <1 <1 7500 (IIIB-a) Polymer <1 <1 <1<1 <1 <1 <1 <1 100 (IIIA-a-2) Comparative polymer 200 <1 <1 <1 <1 <1 <1<1 8000 (IIIc)

Synthesis of Polymerization Initiator and Comparative PolymerizationInitiator, and Comparison of Solubility to Polymerization Solvents

Results of synthesizing polymerization initiators (initiators 2 to 9,11, and 12, and Comparative initiators 1 to 8) other than thepolymerization initiators used above are shown in the following. The“initiator 1” below represents the polymerization initiator synthesizedwith the compound represented by the formula (iA) in the [SynthesisExample 4-1], the polymerization initiator represented by the formula(IA). The “initiator 10” below represents the polymerization initiator(IB) synthesized with the compound represented by the formula (iB) inthe [Synthesis Example 8].

Synthesis of Initiator 2

An initiator 2 was synthesized in the same manner as in the methoddescribed in the [Synthesis Example 2-3] and [Synthesis Example 4-1],except that ethylene glycol used in the [Synthesis Example 2-3] waschanged to diethylene glycol.

Synthesis of Initiator 3

An initiator 3 was synthesized in the same manner as in the methoddescribed in the [Synthesis Example 2-4] and [Synthesis Example 4-1],except that the electrophile (iiB) used in the [Synthesis Example 2-4]was changed to an electrophile (iiC) below.

Synthesis of Initiator 4

An initiator 4 was synthesized in the same manner as in the methoddescribed in the [Synthesis of Initiator 3], except that ethylene glycolused in the [Synthesis Example 2-4] was changed to diethylene glycol.

Synthesis of Initiator 5

An initiator 5 was synthesized in the same manner as in the methoddescribed in the [Synthesis Example 2-4] and [Synthesis Example 4-1],except that the electrophile (iiB) used in the [Synthesis Example 2-4]was changed to an electrophile (iiD) below, and ethylene glycol waschanged to triethylene glycol.

Synthesis of Initiator 6

An initiator 6 was synthesized in the same manner as in the methoddescribed in the [Synthesis Example 2-4] and [Synthesis Example 4-1],except that the electrophile (iiB) used in the [Synthesis Example 2-4]was changed to an electrophile (iiE) below.

In the electrophile (iiE) and the initiator 6, “TBS” meanstert-butyldimethylsilyl

Synthesis of Initiator 7

An initiator 7 was synthesized in the same manner as in the methoddescribed in the [Synthesis Example 2-4] and [Synthesis Example 4-1],except that the electrophile (iiB) used in the [Synthesis Example 2-4]was changed to an electrophile (iiF) below.

Synthesis of Initiator 8

An initiator 8 was synthesized in the same manner as in the methoddescribed in the [Synthesis Example 2-4] and [Synthesis Example 4-1],except that the electrophile (iiB) used in the [Synthesis Example 2-4]was changed to an electrophile (iiG) below.

Synthesis of Initiator 9

An initiator 9 was synthesized in the same manner as in the methoddescribed in the [Synthesis Example 2-4] and [Synthesis Example 4-1],except that the electrophile (iiB) used in the [Synthesis Example 2-4]was changed to an electrophile (iiH) below.

Synthesis of Initiator 11

In a 300 ml three neck flask, 15.7 g of 6-amino-1-hexanol, 91.0 g ofTHF, and 46.3 g of potassium carbonate were charged, and 28.4 ml ofallyl bromide was then dripped therein while the flask was ice-cooledunder a nitrogen atmosphere. Stirring was then performed at nornialtemperature for 1 hour. The reaction liquid was filtered and distilledunder reduced pressure, so that 13.2 g (yield rate 50.0%) of a rawmaterial alcohol (iC) for a polymerization initiator 11 was produced.Subsequently, the polymerization initiator 11 was synthesized in thesame manner as in the method described in the [Synthesis Example 4-1].

Synthesis of Initiator 12

An initiator 12 was synthesized in the same manner as in the [Synthesisof Initiator 11], except that allyl bromide was changed to1,2-bis(chlorodimethylsilyl)ethane.

Synthesis of Comparative Initiator 1

A comparative initiator 1 was synthesized in the same manner as in themethod described in the [Synthesis Example 4-1] using thesilyl-protected amino group-containing alcohol (iiA-2) as a rawmaterial.

Synthesis of Comparative Initiator 2

A comparative initiator 2 was synthesized in the same manner as in themethod described in the [Synthesis of Comparative Initiator 1], exceptthat triethylsilyl as a protective group was changed to trimethylsilyl(TMS).

In the comparative initiator 2, TMS means trimethylsilyl.

Synthesis of Comparative Initiator 3

A comparative initiator 3 was synthesized in the same manner as in themethod described in the [Synthesis of Initiator 11], except that6-amino-1-hexanol used in the [Synthesis of Initiator 11] was changed to3-amino-1-propanol.

Synthesis of Comparative Initiator 4

A comparative initiator 4 was synthesized in the same manner as in themethod described in the [Synthesis Example 4-1], except that thecompound represented by the formula (iD) below was used as a rawmaterial alcohol in place of the compound represented by the formula(iA).

Synthesis of Comparative Initiator 5

A comparative initiator 5 was synthesized in the same manner as in themethod described in the [Synthesis Example 4-1], except that thecompound represented by the formula (iE) below was used as a rawmaterial alcohol in place of the compound represented by the formula(iA).

Synthesis of Comparative Initiator 6

A comparative initiator 6 was synthesized in the same manner as in themethod described in the [Synthesis of Initiator 12], except that6-amino-1-hexanol used in the [Synthesis of Initiator 12] was changed to3-amino-1-propanol.

Synthesis of Comparative Initiator 7

A comparative initiator 7 was synthesized in the same manner as in themethod described in the [Synthesis of Comparative Initiator 3], exceptthat allyl bromide used in the [Synthesis of Comparative Initiator 3]was changed to benzyl bromide.

Synthesis of Comparative Initiator 8

A compound represented by the following formula (iF) was synthesizedthrough the reaction shown in scheme 1 below. A comparative initiator 8was synthesized in the same manner as in the method described in the[Synthesis Example 4-1], except that the compound represented by theformula (iF) was used in place of the compound represented by theformula (iA).

1) Synthesis of Boc-Protected Compound (iF-1)

In a 200 ml three neck flask, 5.11 g of 3-amino-1-propanol, 7.21 g oftriethylamine, 55.43 g of methanol, and 15.61 g of di-tert-butyldicarbonate (hereinafter, written as Boc2O), and stirring was performedunder nitrogen atmosphere at normal temperature for 14 hours. Thereaction of the reaction liquid was stopped with a saturated ammoniumchloride aqueous solution, and extraction with ethyl acetate wasperformed. The obtained ethyl acetate solution was concentrated underreduced pressure, so that 10.73 g of a Boc-protected compound (iF-1) wasproduced (crude yield rate 90%).

2) Synthesis of TBS-Protected Compound (iF-2)

In a 500 ml three neck flask, 10.61 of the Boc-protected compound(iF-1), and 241.80 g of THF were added, and then 9.26 g of imidazole,15.38 g of TBSC1 were added thereto while the flask was ice-cooled undera nitrogen atmosphere. The temperature was brought back to normaltemperature, stirring was then performed for 22 hours, and thereafter,the reaction was stopped with a saturated ammonium chloride aqueoussolution, and extraction with isopropyl ether was performed. Theobtained isopropyl ether solution was concentrated under reducedpressure, so that 18.24 g of a TBS-protected compound (iF-2) wasproduced (crude yield rate 93%).

3) Synthesis of Boc-Protected Compound (iF-3)

In a 500 ml two neck flask, 10.01 g of the TBS-protected compound(iF-2), and 155.58 g of dehydrated THF were added, and 16.68 mL of ann-butyllithium/hexane solution (2.69 M) was dripped therein while theflask was ice-cooled under a nitrogen atmosphere. After stirring wasperformed at the same temperature, 40.87 g of a Boc2O/THF solution (26wt. %) was dripped, the temperature was then brought back to normaltemperature, and stirring was performed for 2.5 hours. The reactionsolution was diluted with isopropyl ether, to be washed with a saturatedammonium chloride aqueous solution, and the obtained solution was thenconcentrated under reduced pressure, so that 14.77 g of a TBS-protectedcompound (iF-3) was produced (crude yield rate 100%).

4) Synthesis of Alcohol (iF)

In a 500 ml three neck flask, 14.77 g of the TBS-protected compound(iF-3) and 110.59 g of THF were charged, and, under nitrogen atmosphere,39.5 mL of a TBAF (tetra-n-butylammonium fluoride)/THF solution wasadded thereto under stirring at normal temperature. After stirring wasperformed at the same temperature for 5 hours, the reaction solution wasdiluted with isopropyl ether, to be washed with ultrapure water. Theobtained isopropyl ether solution was concentrated under reducedpressure, so that 10.22 g of an alcohol (iF) was produced (crude yieldrate 98%).

In the scheme, Boc means tert-butoxycarbonyl

The structures of the various polymerization initiators (initiators 1 to12 and comparative initiators 1 to 8) synthesized above are showntogether below.

Results of solubility of the initiators 1 to 12 and comparativeinitiators 1 to 8 to polymerization solvents are shown below. THF ineach of the products of the initiators 1 to 12 and the comparativeinitiators 1 to 8 synthesized above was distilled away under reducedpressure to extract the polymerization initiators. The results obtainedby dissolving each polymerization initiator in each polymerizationsolvent at a concentration of 20 wt. % are shown. In the case in whichcloudiness was not observed at all in the solution by visualobservation, the initiator was shown as “excellent”; in the case inwhich cloudiness was observed or the initiator did not dissolve at all,or in the case in which the initiator decomposed when the alkoxide wasformed from the initiator, the initiator was shown as “poor”; and theinitiator for which solubility was not checked was shown as “−”.

TABLE 8 THF Toluene Initiators 1 Excellent — 2 Excellent — 3 Excellent —4 Excellent — 5 Excellent — 6 Excellent — 7 Excellent — 8 Excellent — 9Excellent — 10 — Excellent 11 — Excellent 12 — Excellent Comparative 1Poor Poor initiators 2 Poor Poor 3 Poor Poor 4 Poor Poor 5 Poor Poor 6Poor Poor 7 Poor Poor 8 Poor Poor

In studying the synthesis of the comparative initiators 1, 2, 5, and 6,changes in the position protected by a protective group progressed. Onthe other hand, in the initiators 1, 2, 6, 7, 10, and 12 in which chainlengths were extended, the initiators stably existed and dissolved inthe solvent. In addition, the comparative initiators 3, 4, 7, and 8 didnot dissolve in the solvents. On the other hand, the initiators 3, 4, 5,8, 9, and 11, in which the chain lengths were extended, dissolved in asolvent.

From the results of the above-described Examples and ComparativeExamples, it is revealed that, in the [Synthesis Example 5] and in the[Comparative Synthesis Example 1], the latter requires a longpolymerization time, as long as 80 hours, due to the presence of analcohol as an initiator raw material, and that, in the former, thepolymerization reaction is completed within 8 hours by using aninitiator that is soluble in THF even in a state in which the amount ofresidual alcohol as an initiator raw material is small. That is to say,the polymerization of an alkylene oxide under mild conditions wasrealized by the method of the present invention. Moreover, by using thereaction liquid in the Synthesis Example 5, without performingpost-treatment, directly to the reaction in the subsequent step in theSynthesis Example 6, the process was able to be substantiallysimplified. Furthermore, by using an organic solvent for purifying aresin with an ion exchange resin in the Synthesis Example 12, it becamepossible to purify a polymer by a simple method without using freeze dryin the final process.

In the [Synthesis Examples 5 to 8] and the [Comparative Examples 1 to3], hydrogenation reaction using a heavy metal as a catalyst is requiredfor reducing a cyano group in the latter; however, in the former, thetarget polymer can be synthesized only by deprotecting the protectedamino group. In the comparative polymer (Inc), β-elimination ofacrylonitrile and production of secondary and tertiary amines occurredthrough hydrogen reduction; however, in the example polymers (IIIA-a),(IIIB-a), and

(IIIA-a-2), production of any one of them was not observed (Table 6).Moreover, from the results of metal analysis, it is revealed that, inthe [Synthesis Examples 7-1, 8, and 12], and in the [ComparativeSynthesis Example 3], the heavy metal used for reduction is mixed in thecomparative polymer, but that a heavy metal is not substantially mixedin the example polymers because a heavy metal is not used in the[Synthesis Examples 7-1, 8, and 12]. Moreover, the amount of a potassiummetal mixed was able to be reduced by the purification with a strongacid cation exchange resin (Table 7). As a result thereof, synthesis ofa narrowly distributed and amino group-containing polyalkylene glycolderivative without mixing of a heavy metal that could cause adverseeffects in medical supplies was able to be achieved by the presentinvention. Moreover, novel protected amino-group containing alcoholswere synthesized, and further, polymerization initiators were producedusing the alcohols as a raw material, and thereby it became possible toapply the polymerization initiators for synthesis of various polymers.By using the novel polymerization initiators, and further performingpurification with a cation exchange resin as needed, it became possibleto remove diol polymers produced due to mixing of water and that hadbeen difficult to separate, thereby making it possible to producenarrowly distributed amino group-containing polyalkylene glycolderivatives with high purity to enlarge a production margin.

Polymer compounds produced using the method of the present invention canwidely be used as a starting raw material in synthesizing blockcopolymers for use in medical supplies and cosmetic products including afield of drug delivery systems. Moreover, metal salts of novel protectedamino group-containing alcohols can be applied to synthesis of variouspolymers.

Having thus described certain embodiments of the present invention, itis to be understood that the invention defined by the appended claims isnot to be limited by particular details set forth in the abovedescription as many apparent variations thereof are possible withoutdeparting from the spirit or scope thereof as hereinafter claimed.

What is claimed is:
 1. A silyl-protected amino group-containing alcoholcompound of formula (6) or (7):

wherein each R¹ independently is a linear monovalent hydrocarbon grouphaving 1 to 6 carbon atoms, or a branched or cyclic monovalenthydrocarbon group having 3 to 6 carbon atoms, or R¹ may bind to eachother to form a 3 to 6 membered ring together with a silicon atom havingbonds with R¹; R² is a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms; R³ is a linear divalent hydrocarbon group having 4to 6 carbon atoms; R⁵ is an alkylene group having 2 to 8 carbon atoms,and R⁵ is not the same as R²; and m is an integer of 1 to
 3. 2. A metalsalt of a silyl-protected amino group-containing alcohol compound offormula (1) or (2):

wherein each R¹ independently is a linear monovalent hydrocarbon grouphaving 1 to 6 carbon atoms, or a branched or cyclic monovalenthydrocarbon group having 3 to 6 carbon atoms, or R¹ may bind to eachother to form a 3 to 6 membered ring together with a silicon atom havingbonds with R¹; R² is a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms; R³ is a linear divalent hydrocarbon group having 4to 6 carbon atoms; R⁵ is an alkylene group having 2 to 8 carbon atoms,and R⁵ is not the same as R²; M is an alkali metal; and m is an integerof 1 to
 3. 3. A polyalkylene compound derivative having a protectedamino group of formula (II-1) or (II-2):

wherein each R¹ independently is a linear monovalent hydrocarbon grouphaving 1 to 6 carbon atoms, or a branched or cyclic monovalenthydrocarbon group having 3 to 6 carbon atoms, or R¹ may bind to eachother to form a 3 to 6 membered ring together with a silicon atom havingbonds with R¹; R² is a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms; R³ is a linear divalent hydrocarbon group having 4to 6 carbon atoms; R⁴ is a hydrogen atom, or a linear, branched, orcyclic hydrocarbon group that may be substituted, the hydrocarbon grouphaving 1 to 12 carbon atoms, and the hydrocarbon group may contain aheteroatom; R⁵ is an alkylene group having 2 to 8 carbon atoms, and R⁵is not the same as R²; m is an integer of 1 to 3; and n is an integer of1 to 450.